T Lymphocytes in Cell-Mediated Immunity
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Questions and Answers

What is the main challenge faced by naive T cells in generating a useful cell-mediated immune response?

  • Distinguishing between microbial and harmless proteins
  • Finding the correct type of antigen
  • Finding the antigen (correct)
  • Responding to all types of antigens

    • What is the role of APCs in solving the problem of naive T cells finding the antigen?

  • They destroy the antigen
  • They ignore the antigen
  • They only respond to CD4+ helper T cells
  • They capture and concentrate the antigen in specialized lymphoid organs (correct)

    • What determines the selectivity of T lymphocytes in responding to antigens from endosomal and cytosolic compartments?

  • The specificity of CD4 and CD8 coreceptors for class II and class I MHC molecules (correct)
  • The type of antigen presented
  • The location of the antigen
  • The strength of the immune response

    • Why do T cells respond to microbial antigens but not to harmless proteins?

    <p>Because T cell activation requires costimulators that are induced on APCs by microbes</p> Signup and view all the answers

    What is the role of CD4+ helper T cells in the immune response?

    <p>They respond to antigens from the endosomal compartment</p> Signup and view all the answers

    What is the role of CD8+ CTLs in the immune response?

    <p>They respond to antigens from the cytosolic compartment</p> Signup and view all the answers

    What is the mechanism by which T cells distinguish between microbial and harmless proteins?

    <p>T cell activation requires costimulators that are induced on APCs by microbes</p> Signup and view all the answers

    What is the role of MHC molecules in the immune response?

    <p>They present antigens to T cells</p> Signup and view all the answers

    What is the location where naive T cells recirculate and encounter APCs?

    <p>Lymphoid organs</p> Signup and view all the answers

    What is the purpose of antigen recognition by T cells?

    <p>To respond to microbial antigens but not to harmless proteins</p> Signup and view all the answers

    What is the primary function of APCs in the cell-mediated immune response?

    <p>To capture and concentrate antigens in lymphoid organs</p> Signup and view all the answers

    What determines the specificity of T cell responses to antigens from endosomal and cytosolic compartments?

    <p>The expression of CD4 and CD8 coreceptors on T cells</p> Signup and view all the answers

    Why do T cells respond to microbial antigens but not to harmless proteins?

    <p>Because T cell activation requires costimulators induced by microbes</p> Signup and view all the answers

    What is the primary role of CD4+ helper T cells in the cell-mediated immune response?

    <p>To activate CD8+ CTLs</p> Signup and view all the answers

    Where do naive T cells recirculate and encounter APCs?

    <p>In the lymphoid organs</p> Signup and view all the answers

    What is the function of class II MHC molecules?

    <p>To present antigens from the endosomal compartment</p> Signup and view all the answers

    What is the role of costimulators in T cell activation?

    <p>To induce T cell activation in response to microbial antigens</p> Signup and view all the answers

    What is the primary function of CD8+ CTLs in the cell-mediated immune response?

    <p>To recognize and eliminate microbial antigens</p> Signup and view all the answers

    What is the mechanism by which T cells distinguish between antigens from endosomal and cytosolic compartments?

    <p>Through the expression of class I and class II MHC molecules on APCs</p> Signup and view all the answers

    What is the primary function of antigen recognition by T cells?

    <p>To initiate a cell-mediated immune response</p> Signup and view all the answers

    What is the primary function of APCs in the cell-mediated immune response?

    <p>To capture and concentrate antigen in lymphoid organs</p> Signup and view all the answers

    What determines the specificity of T cell responses to antigens from endosomal and cytosolic compartments?

    <p>The type of MHC molecule involved</p> Signup and view all the answers

    Why do T cells respond to microbial antigens but not to harmless proteins?

    <p>Because costimulators are induced by microbes</p> Signup and view all the answers

    What is the role of CD4+ helper T cells in the immune response?

    <p>To provide help to B cells for antibody production</p> Signup and view all the answers

    Where do naive T cells recirculate and encounter APCs?

    <p>In lymphoid organs</p> Signup and view all the answers

    What is the primary function of class I MHC molecules?

    <p>To present antigen to CD8+ T cells</p> Signup and view all the answers

    What is the role of costimulators in T cell activation?

    <p>To provide a second signal for T cell activation</p> Signup and view all the answers

    What is the primary function of CD8+ CTLs?

    <p>To directly kill infected cells</p> Signup and view all the answers

    How do APCs solve the problem of naive T cells finding the antigen?

    <p>By capturing and concentrating antigen in lymphoid organs</p> Signup and view all the answers

    What determines the selectivity of T lymphocytes in responding to antigens from endosomal and cytosolic compartments?

    <p>The type of MHC molecule involved</p> Signup and view all the answers

    What is the primary function of APCs in the cell-mediated immune response?

    <p>To capture and concentrate antigen in lymphoid organs</p> Signup and view all the answers

    How do T cells distinguish between microbial and harmless proteins?

    <p>Through the presence of costimulators on APCs</p> Signup and view all the answers

    What determines the specificity of CD4+ helper T cells?

    <p>The specificity of the CD4 coreceptor for class II MHC molecules</p> Signup and view all the answers

    What is the role of class I MHC molecules?

    <p>To present antigens from the cytosolic compartment</p> Signup and view all the answers

    Where do naive T cells recirculate and encounter APCs?

    <p>In lymphoid organs</p> Signup and view all the answers

    What is the purpose of antigen recognition by T cells?

    <p>To initiate a cell-mediated immune response</p> Signup and view all the answers

    What determines the selectivity of T lymphocytes in responding to antigens?

    <p>The specificity of the CD4 and CD8 coreceptors for class II and class I MHC molecules</p> Signup and view all the answers

    What is the function of CD8+ CTLs?

    <p>To lyse infected cells</p> Signup and view all the answers

    What is the role of costimulators in T cell activation?

    <p>To induce T cell activation</p> Signup and view all the answers

    What is the mechanism by which T cells respond to microbial antigens?

    <p>Through the presence of costimulators on APCs</p> Signup and view all the answers

    What is the primary function of APCs in relation to naive T cells?

    <p>To capture and concentrate antigens in lymphoid organs</p> Signup and view all the answers

    Which type of T cells responds to antigens from the cytosolic compartment?

    <p>CD8+ CTLs</p> Signup and view all the answers

    What is the role of MHC molecules in T cell activation?

    <p>To present antigens to T cells</p> Signup and view all the answers

    What is necessary for T cell activation in response to microbial antigens?

    <p>Costimulators induced on APCs by microbes</p> Signup and view all the answers

    What is the primary function of CD4+ helper T cells in the immune response?

    <p>To recognize and respond to antigens from the endosomal compartment</p> Signup and view all the answers

    Which type of T cells responds to antigens from the endosomal compartment?

    <p>CD4+ helper T cells</p> Signup and view all the answers

    What is the role of CD8 coreceptors in T cell activation?

    <p>To recognize antigens from the cytosolic compartment</p> Signup and view all the answers

    What is the primary function of class II MHC molecules in the immune response?

    <p>To present antigens from the endosomal compartment</p> Signup and view all the answers

    What is the mechanism by which T cells respond to antigens from the endosomal compartment?

    <p>Recognition of antigens by CD4+ helper T cells</p> Signup and view all the answers

    What is the primary function of costimulators in T cell activation?

    <p>To provide a second signal for T cell activation</p> Signup and view all the answers

    What is the primary function of antigen-presenting cells (APCs) in the cell-mediated immune response?

    <p>To capture and concentrate antigens for naive T cell recognition</p> Signup and view all the answers

    What determines the selectivity of T lymphocytes in responding to antigens from endosomal and cytosolic compartments?

    <p>The specificity of CD4 and CD8 coreceptors for class II and class I MHC molecules</p> Signup and view all the answers

    Why do T cells respond to microbial antigens but not to harmless proteins?

    <p>Because microbial antigens induce costimulators on APCs</p> Signup and view all the answers

    What is the role of class II MHC molecules in the immune response?

    <p>To present antigens from the endosomal compartment to CD4+ helper T cells</p> Signup and view all the answers

    Where do naive T cells recirculate and encounter antigen-presenting cells (APCs)?

    <p>In specialized lymphoid organs</p> Signup and view all the answers

    What is necessary for T cell activation in response to microbial antigens?

    <p>The presence of costimulators on APCs</p> Signup and view all the answers

    Which type of T cell responds to antigens from the cytosolic compartment?

    <p>CD8+ CTLs</p> Signup and view all the answers

    What is the mechanism by which T cells distinguish between microbial and harmless proteins?

    <p>The expression of costimulators on APCs</p> Signup and view all the answers

    What is the primary function of costimulators in T cell activation?

    <p>To provide a second signal for T cell activation</p> Signup and view all the answers

    What is the role of CD4 coreceptors in T cell activation?

    <p>To facilitate the interaction between T cells and APCs</p> Signup and view all the answers

    What is the primary function of APCs in the generation of a cell-mediated immune response?

    <p>To capture and concentrate antigens for presentation to naive T cells</p> Signup and view all the answers

    What determines the selectivity of CD4+ helper T cells in responding to antigens?

    <p>The specificity of CD4 coreceptors for class II MHC molecules</p> Signup and view all the answers

    Why do T cells respond to microbial antigens but not to harmless proteins?

    <p>Because T cells require costimulators induced by microbes</p> Signup and view all the answers

    What is the primary function of class I MHC molecules in the immune response?

    <p>To present antigens from the cytosolic compartment to CD8+ CTLs</p> Signup and view all the answers

    What is the role of costimulators in T cell activation?

    <p>To provide a second signal for T cell activation</p> Signup and view all the answers

    What is the primary function of CD8+ CTLs in the immune response?

    <p>To eliminate infected cells</p> Signup and view all the answers

    Where do naive T cells recirculate and encounter APCs?

    <p>In specialized lymphoid organs</p> Signup and view all the answers

    What is the primary function of class II MHC molecules in the immune response?

    <p>To present antigens from the endosomal compartment to CD4+ helper T cells</p> Signup and view all the answers

    What is the mechanism by which T cells respond to antigens from the endosomal compartment?

    <p>Through recognition of class II MHC molecules</p> Signup and view all the answers

    What is the primary function of antigen recognition by T cells?

    <p>To initiate a cell-mediated immune response</p> Signup and view all the answers

    What is the primary function of antigen-presenting cells (APCs) in the cell-mediated immune response?

    <p>To capture and concentrate antigens for presentation to T cells</p> Signup and view all the answers

    Which of the following is a characteristic of CD4+ helper T cells?

    <p>They respond to antigens from the endosomal compartment</p> Signup and view all the answers

    What is the role of costimulators in T cell activation?

    <p>To provide a secondary signal for T cell activation</p> Signup and view all the answers

    Which type of MHC molecule is involved in presenting antigens from the endosomal compartment?

    <p>Class II MHC molecules</p> Signup and view all the answers

    What is the purpose of antigen recognition by T cells?

    <p>To mount a cell-mediated immune response against microbes</p> Signup and view all the answers

    Why do T cells respond to microbial antigens but not to harmless proteins?

    <p>Because T cells are activated by costimulators induced by microbes</p> Signup and view all the answers

    Which of the following is a characteristic of CD8+ CTLs?

    <p>They respond to antigens from the cytosolic compartment</p> Signup and view all the answers

    What is the primary function of class I MHC molecules?

    <p>To present antigens from the cytosolic compartment</p> Signup and view all the answers

    Where do naive T cells recirculate and encounter APCs?

    <p>In the lymph nodes</p> Signup and view all the answers

    What is the mechanism by which T cells distinguish between antigens from the endosomal and cytosolic compartments?

    <p>Through the segregation of extracellular and intracellular protein antigens</p> Signup and view all the answers

    What is the main function of APCs in the generation of a useful cell-mediated immune response?

    <p>To capture and concentrate antigens in specialized lymphoid organs</p> Signup and view all the answers

    Which type of T cells respond to antigens from the cytosolic compartment?

    <p>CD8+ CTLs</p> Signup and view all the answers

    What is the purpose of costimulators in T cell activation?

    <p>To induce T cell activation in response to microbial antigens</p> Signup and view all the answers

    How do T cells distinguish between microbial and harmless proteins?

    <p>Through the presence of costimulators on APCs</p> Signup and view all the answers

    What is the role of CD4 coreceptors in T cell activation?

    <p>To bind to class II MHC molecules on APCs</p> Signup and view all the answers

    Where do naive T cells recirculate and encounter APCs?

    <p>In specialized lymphoid organs</p> Signup and view all the answers

    What is the function of class I MHC molecules?

    <p>To present antigens to CD8+ T cells</p> Signup and view all the answers

    What is necessary for T cell activation in response to microbial antigens?

    <p>Presence of costimulators on APCs</p> Signup and view all the answers

    Which type of T cells respond to antigens from the endosomal compartment?

    <p>CD4+ helper T cells</p> Signup and view all the answers

    What determines the selectivity of T lymphocytes in responding to antigens from endosomal and cytosolic compartments?

    <p>The specificity of CD4 and CD8 coreceptors</p> Signup and view all the answers

    What is the primary function of CD4 and CD8 coreceptors in T cell activation?

    <p>To provide selectivity for T lymphocytes in responding to antigens from endosomal and cytosolic compartments</p> Signup and view all the answers

    What is the primary function of antigen presentation by APCs?

    <p>To concentrate antigens in specialized lymphoid organs for naive T cells to encounter</p> Signup and view all the answers

    What is the primary function of class I MHC molecules in T cell activation?

    <p>To present antigens from the cytosolic compartment to CD8+ CTLs</p> Signup and view all the answers

    What determines the specificity of T cell responses to antigens from endosomal and cytosolic compartments?

    <p>The segregation of extracellular and intracellular protein antigens for display by class II and class I MHC molecules</p> Signup and view all the answers

    What is the primary function of costimulators in T cell activation?

    <p>To induce T cell activation in response to microbial antigens</p> Signup and view all the answers

    Where do naive T cells recirculate and encounter APCs?

    <p>In specialized lymphoid organs</p> Signup and view all the answers

    What determines the selectivity of CD4+ helper T cells in responding to antigens?

    <p>The segregation of extracellular and intracellular protein antigens for display by class II and class I MHC molecules</p> Signup and view all the answers

    What is the primary function of CD8+ CTLs in the immune response?

    <p>To recognize and respond to antigens from the cytosolic compartment</p> Signup and view all the answers

    What is necessary for T cell activation in response to microbial antigens?

    <p>The presence of costimulators on APCs</p> Signup and view all the answers

    What is the primary function of class II MHC molecules in T cell activation?

    <p>To present antigens from the endosomal compartment to CD4+ helper T cells</p> Signup and view all the answers

    Which cells are responsible for capturing and concentrating antigens in specialized lymphoid organs?

    <p>APCs</p> Signup and view all the answers

    What is the main function of CD4 and CD8 coreceptors in T cells?

    <p>To determine the specificity of T cells for class II and class I MHC molecules</p> Signup and view all the answers

    Why do T cells respond to microbial antigens but not to harmless proteins?

    <p>Because T cells are activated by costimulators induced by microbes</p> Signup and view all the answers

    Which of the following is a mechanism that has evolved to overcome the challenges of generating a useful cell-mediated immune response?

    <p>APCs capturing and concentrating antigens</p> Signup and view all the answers

    What is the result of the segregation of extracellular and intracellular protein antigens for display by class II and class I MHC molecules?

    <p>T cells respond to both antigens from the endosomal and cytosolic compartments</p> Signup and view all the answers

    What is necessary for T cell activation in response to antigens?

    <p>Costimulators induced by microbes</p> Signup and view all the answers

    Which type of T cells responds to antigens from the endosomal compartment?

    <p>CD4+ helper T cells</p> Signup and view all the answers

    What is the function of MHC molecules in the immune response?

    <p>To present antigens to T cells</p> Signup and view all the answers

    Why do T cells respond to antigens from the cytosolic compartment?

    <p>Because antigens from the cytosolic compartment are presented by class I MHC molecules</p> Signup and view all the answers

    What is the primary function of APCs in the cell-mediated immune response?

    <p>To capture and concentrate antigens in lymphoid organs</p> Signup and view all the answers

    What is the primary function of antigen-presenting cells (APCs) in the cell-mediated immune response?

    <p>To capture and concentrate antigens for naive T cells</p> Signup and view all the answers

    Why do T cells respond to microbial antigens but not to harmless proteins?

    <p>Because microbial antigens induce costimulators on APCs</p> Signup and view all the answers

    What determines the specificity of T cell responses to antigens from endosomal and cytosolic compartments?

    <p>The type of MHC molecule involved</p> Signup and view all the answers

    What is the role of CD4+ helper T cells in the immune response?

    <p>To provide help to CD8+ CTLs</p> Signup and view all the answers

    What is the function of class I MHC molecules?

    <p>To present antigens from the cytosolic compartment</p> Signup and view all the answers

    What is required for T cell activation in response to microbial antigens?

    <p>The presence of costimulators on APCs</p> Signup and view all the answers

    What is the role of CD8+ CTLs in the immune response?

    <p>To recognize and eliminate infected cells</p> Signup and view all the answers

    What determines the selectivity of T lymphocytes in responding to antigens from the endosomal and cytosolic compartments?

    <p>The type of MHC molecule involved</p> Signup and view all the answers

    What is the mechanism by which T cells distinguish between microbial and harmless proteins?

    <p>Through the presence of costimulators on APCs</p> Signup and view all the answers

    Where do naive T cells recirculate and encounter APCs?

    <p>In lymphoid organs</p> Signup and view all the answers

    Study Notes

    T Lymphocytes and Cell-Mediated Immunity

    • T lymphocytes perform multiple functions in defending against infections by various kinds of microbes.
    • They play a major role in cell-mediated immunity, which provides defense against infections by intracellular microbes.
    • Cell-mediated immunity is necessary to eliminate infections that occur inside cells, such as those caused by viruses and some bacteria.

    Phases of T Cell Responses

    • Naive T lymphocytes recognize antigens in peripheral lymphoid organs, which initiates proliferation and differentiation into effector and memory cells.
    • Effector cells perform their functions when they are activated by the same antigens in peripheral tissues or lymphoid organs.
    • The responses of naive T lymphocytes to cell-associated microbial antigens consist of a series of sequential steps, including:
      • Antigen recognition
      • Cytokine secretion and receptor expression
      • Clonal expansion
      • Differentiation into effector and memory cells

    Antigen Recognition and Costimulation

    • The initiation of T cell responses requires multiple receptors on the T cells recognizing ligands on antigen-presenting cells (APCs).
    • The T cell receptor (TCR) recognizes MHC-associated peptide antigens.
    • CD4 or CD8 coreceptors on the T cells recognize MHC molecules on the APC and help the TCR complex to deliver activating signals.
    • Adhesion molecules strengthen the binding of T cells to APCs.
    • Costimulators, such as B7-1 and B7-2, on APCs promote the responses of T cells to antigens.
    • Cytokines amplify the T cell response and direct it along various differentiation pathways.

    Role of Adhesion Molecules and Costimulation

    • Adhesion molecules, such as integrins, on T cells recognize ligands on APCs and stabilize the binding of T cells to APCs.
    • The binding of T cells to APCs must be stabilized for a sufficiently long period to achieve the necessary signaling threshold.
    • Costimulation ensures that naive T lymphocytes are activated fully by microbial antigens and not by harmless foreign substances or self-antigens.

    Inhibitory Receptors of T Cells

    • Inhibitory receptors, such as CTLA-4 and PD-1, are critical for limiting and terminating immune responses.
    • These receptors function to terminate responses of activated T cells and prevent immune responses against self-antigens.
    • Genetic deletion or blockade of these molecules can result in systemic autoimmune disease.

    Stimuli for Activation of CD8+ T Cells

    • The activation of CD8+ T cells is stimulated by recognition of class I MHC-associated peptides and requires costimulation and helper T cells.
    • The initiation of CD8+ T cell activation often requires cytosolic antigen from one cell (e.g., virus-infected or tumor cells) to be cross-presented by dendritic cells.
    • The differentiation of naive CD8+ T cells into fully active cytotoxic T lymphocytes (CTLs) and memory cells may require the concomitant activation of CD4+ helper T cells.### Helper T Cells and CD8+ T Cells
    • Human immunodeficiency virus (HIV) kills CD4+ but not CD8+ T cells, which is likely the explanation for the defective CTL responses to many viruses in HIV patients.
    • CD8+ T cells can respond to some viruses without the help of CD4+ T cells.

    Biochemical Pathways of T Cell Activation

    • T cell activation leads to protein synthesis, differentiation, and effector functions.
    • Antigen recognition triggers several biochemical mechanisms, including:
      • Kinase activation
      • Adaptor protein recruitment
      • Production of active transcription factors
    • The TCR complex, CD4/CD8 coreceptors, and CD28 coalesce at the center of the immune synapse, while integrins move to the periphery.
    • The immune synapse is required for optimal induction of activating signals in the T cell.

    Signaling Pathways

    • CD4 and CD8 coreceptors facilitate signaling through the protein tyrosine kinase Lck.
    • Lck phosphorylates ITAMs (immunoreceptor tyrosine-based activation motifs) in the CD3 and ζ chains.
    • The phosphorylated ITAMs in the ζ chain become docking sites for the tyrosine kinase ZAP-70.
    • ZAP-70 phosphorylates various adaptor proteins and enzymes, leading to additional signaling events.
    • The major signaling pathways linked to ζ-chain phosphorylation and ZAP-70 are:
      • Calcium-NFAT pathway
      • Ras- and Rac-MAP kinase pathways
      • PKCθ-NF-κB pathway
      • PI-3 kinase pathway

    Calcium-NFAT Pathway

    • NFAT (nuclear factor of activated T cells) is a transcription factor that is present in an inactive form in the cytoplasm of resting T cells.
    • NFAT activation and nuclear translocation depend on the concentration of Ca2+ ions in the cytosol.
    • The signaling pathway is initiated by ZAP-70-mediated phosphorylation and activation of phospholipase Cγ (PLCγ).
    • PLCγ catalyzes the hydrolysis of PIP2, generating IP3, which binds to IP3 receptors on the ER membrane, stimulating the release of Ca2+ from the ER.

    Ras- and Rac-MAP Kinase Pathways

    • These pathways are initiated by ZAP-70-dependent phosphorylation and accumulation of adaptor proteins at the plasma membrane.
    • The pathways lead to the activation of distinct MAP kinases (ERK and JNK), which induce the expression of the transcription factor AP-1.

    PKCθ-NF-κB Pathway

    • PKCθ is activated by diacylglycerol, which is generated by PLC-mediated hydrolysis of membrane inositol lipids.
    • PKCθ acts through adaptor proteins recruited to the TCR complex to activate NF-κB.
    • NF-κB is released from its inhibitor IκB and moves to the nucleus, promoting the transcription of several genes.

    PI-3 Kinase Pathway

    • PI-3 kinase phosphorylates the membrane phospholipid PIP2 to generate PIP3.
    • PIP3 is required for the activation of Akt, which has many roles, including stimulating the expression of antiapoptotic proteins and promoting survival of antigen-stimulated T cells.

    T Cell Functional Responses

    • T cell activation leads to the secretion of cytokines, such as IL-2, which act on the T cells themselves and on other cells involved in immune defenses.
    • Cytokines are produced by effector T cells and serve diverse roles in host defense.
    • IL-2 is produced by activated CD4+ T cells and stimulates the survival and proliferation of T cells.
    • The IL-2 receptor is a three-chain molecule, and its expression is increased on activated T cells.

    Clonal Expansion

    • T lymphocytes activated by antigen and costimulation begin to proliferate, resulting in the expansion of antigen-specific clones.
    • The magnitude of clonal expansion is remarkable, especially for CD8+ T cells.
    • The expansion of CD4+ T cells is 100- to 1000-fold less than that of CD8+ cells.

    Differentiation of Naive T Cells into Effector Cells

    • Some of the progeny of antigen-stimulated, proliferating T cells differentiate into effector cells whose function is to eradicate infections.
    • Effector cells of the CD4+ lineage acquire the capacity to produce different sets of cytokines.
    • Effector cells of the CD8+ lineage acquire the ability to kill infected cells.

    Development of Memory T Lymphocytes

    • A fraction of antigen-activated T lymphocytes differentiates into long-lived memory cells.
    • Memory cells survive even after the infection is eradicated and antigen is no longer present.
    • Memory cells can be found in lymphoid organs, peripheral tissues, and the circulation.

    Migration of T Lymphocytes in Cell-Mediated Immune Reactions

    • T cells at different stages of their lives have to migrate in different ways.
    • Naive T cells migrate between blood and secondary lymphoid organs through HEVs (high endothelial venules).
    • HEVs are lined by specialized endothelial cells that express carbohydrate ligands that bind to L-selectin.### Migration of Naive T Cells
    • Naive T cells migrate through blood vessels in a multistep sequence similar to other leukocytes
    • Engagement of L-selectin with HEV (high endothelial venules) allows chemokines to bind to CCR7 on T cells
    • CCR7 transduces signals that activate LFA-1 (leukocyte function-associated antigen 1) on naive T cells, increasing binding affinity for ICAM-1 on HEV
    • Firm adhesion and arrest of rolling T cells occurs, followed by exit into the T cell zone of the lymph node

    Egress of T Cells from Lymph Nodes

    • Sphingosine 1-phosphate (S1P) plays a key role in T cell egress from lymph nodes
    • S1P levels are higher in blood and lymph than inside lymph nodes
    • S1P binds to its receptor, reducing expression on circulating naive T cells
    • When a naive T cell enters a node, S1P receptor expression increases, and the cell exits the node through efferent lymphatic vessels following the S1P gradient

    Activation and Differentiation of T Cells

    • Activated T cells do not express CCR7 or L-selectin, preventing re-entry into lymph nodes
    • Effector T cells migrate to sites of infection, expressing adhesion molecules and chemokine receptors that bind to ligands on vascular endothelium
    • Naive T cells do not express ligands for E- or P-selectin or receptors for chemokines produced at inflammatory sites, preventing migration into sites of infection

    Site-Specific Immune Response

    • Homing of effector T cells to a site of infection is independent of antigen recognition, but lymphocytes that recognize antigens are preferentially retained and activated at the site
    • Chemokines produced by macrophages and endothelial cells stimulate motility of transmigrating T cells
    • Effector T cells that leave the circulation and recognize microbial antigens presented by local tissue APCs become reactivated and contribute to killing microbes

    Decline of the Immune Response

    • After an infection is cleared, the immune response subsides, and the system returns to homeostasis
    • Survival and proliferation of T cells are maintained by antigen, costimulatory signals from CD28, and cytokines like IL-2
    • Once the infection is cleared, stimulated T cells die by apoptosis, and the response subsides within 1-2 weeks

    T Lymphocytes and Cell-Mediated Immunity

    • T lymphocytes perform multiple functions in defending against infections by various kinds of microbes.
    • They play a major role in cell-mediated immunity, which provides defense against infections by intracellular microbes.
    • Cell-mediated immunity is necessary to eliminate infections that occur inside cells, such as those caused by viruses and some bacteria.

    Phases of T Cell Responses

    • Naive T lymphocytes recognize antigens in peripheral lymphoid organs, which initiates proliferation and differentiation into effector and memory cells.
    • Effector cells perform their functions when they are activated by the same antigens in peripheral tissues or lymphoid organs.
    • The responses of naive T lymphocytes to cell-associated microbial antigens consist of a series of sequential steps, including:
      • Antigen recognition
      • Cytokine secretion and receptor expression
      • Clonal expansion
      • Differentiation into effector and memory cells

    Antigen Recognition and Costimulation

    • The initiation of T cell responses requires multiple receptors on the T cells recognizing ligands on antigen-presenting cells (APCs).
    • The T cell receptor (TCR) recognizes MHC-associated peptide antigens.
    • CD4 or CD8 coreceptors on the T cells recognize MHC molecules on the APC and help the TCR complex to deliver activating signals.
    • Adhesion molecules strengthen the binding of T cells to APCs.
    • Costimulators, such as B7-1 and B7-2, on APCs promote the responses of T cells to antigens.
    • Cytokines amplify the T cell response and direct it along various differentiation pathways.

    Role of Adhesion Molecules and Costimulation

    • Adhesion molecules, such as integrins, on T cells recognize ligands on APCs and stabilize the binding of T cells to APCs.
    • The binding of T cells to APCs must be stabilized for a sufficiently long period to achieve the necessary signaling threshold.
    • Costimulation ensures that naive T lymphocytes are activated fully by microbial antigens and not by harmless foreign substances or self-antigens.

    Inhibitory Receptors of T Cells

    • Inhibitory receptors, such as CTLA-4 and PD-1, are critical for limiting and terminating immune responses.
    • These receptors function to terminate responses of activated T cells and prevent immune responses against self-antigens.
    • Genetic deletion or blockade of these molecules can result in systemic autoimmune disease.

    Stimuli for Activation of CD8+ T Cells

    • The activation of CD8+ T cells is stimulated by recognition of class I MHC-associated peptides and requires costimulation and helper T cells.
    • The initiation of CD8+ T cell activation often requires cytosolic antigen from one cell (e.g., virus-infected or tumor cells) to be cross-presented by dendritic cells.
    • The differentiation of naive CD8+ T cells into fully active cytotoxic T lymphocytes (CTLs) and memory cells may require the concomitant activation of CD4+ helper T cells.### Helper T Cells and CD8+ T Cells
    • Human immunodeficiency virus (HIV) kills CD4+ but not CD8+ T cells, which is likely the explanation for the defective CTL responses to many viruses in HIV patients.
    • CD8+ T cells can respond to some viruses without the help of CD4+ T cells.

    Biochemical Pathways of T Cell Activation

    • T cell activation leads to protein synthesis, differentiation, and effector functions.
    • Antigen recognition triggers several biochemical mechanisms, including:
      • Kinase activation
      • Adaptor protein recruitment
      • Production of active transcription factors
    • The TCR complex, CD4/CD8 coreceptors, and CD28 coalesce at the center of the immune synapse, while integrins move to the periphery.
    • The immune synapse is required for optimal induction of activating signals in the T cell.

    Signaling Pathways

    • CD4 and CD8 coreceptors facilitate signaling through the protein tyrosine kinase Lck.
    • Lck phosphorylates ITAMs (immunoreceptor tyrosine-based activation motifs) in the CD3 and ζ chains.
    • The phosphorylated ITAMs in the ζ chain become docking sites for the tyrosine kinase ZAP-70.
    • ZAP-70 phosphorylates various adaptor proteins and enzymes, leading to additional signaling events.
    • The major signaling pathways linked to ζ-chain phosphorylation and ZAP-70 are:
      • Calcium-NFAT pathway
      • Ras- and Rac-MAP kinase pathways
      • PKCθ-NF-κB pathway
      • PI-3 kinase pathway

    Calcium-NFAT Pathway

    • NFAT (nuclear factor of activated T cells) is a transcription factor that is present in an inactive form in the cytoplasm of resting T cells.
    • NFAT activation and nuclear translocation depend on the concentration of Ca2+ ions in the cytosol.
    • The signaling pathway is initiated by ZAP-70-mediated phosphorylation and activation of phospholipase Cγ (PLCγ).
    • PLCγ catalyzes the hydrolysis of PIP2, generating IP3, which binds to IP3 receptors on the ER membrane, stimulating the release of Ca2+ from the ER.

    Ras- and Rac-MAP Kinase Pathways

    • These pathways are initiated by ZAP-70-dependent phosphorylation and accumulation of adaptor proteins at the plasma membrane.
    • The pathways lead to the activation of distinct MAP kinases (ERK and JNK), which induce the expression of the transcription factor AP-1.

    PKCθ-NF-κB Pathway

    • PKCθ is activated by diacylglycerol, which is generated by PLC-mediated hydrolysis of membrane inositol lipids.
    • PKCθ acts through adaptor proteins recruited to the TCR complex to activate NF-κB.
    • NF-κB is released from its inhibitor IκB and moves to the nucleus, promoting the transcription of several genes.

    PI-3 Kinase Pathway

    • PI-3 kinase phosphorylates the membrane phospholipid PIP2 to generate PIP3.
    • PIP3 is required for the activation of Akt, which has many roles, including stimulating the expression of antiapoptotic proteins and promoting survival of antigen-stimulated T cells.

    T Cell Functional Responses

    • T cell activation leads to the secretion of cytokines, such as IL-2, which act on the T cells themselves and on other cells involved in immune defenses.
    • Cytokines are produced by effector T cells and serve diverse roles in host defense.
    • IL-2 is produced by activated CD4+ T cells and stimulates the survival and proliferation of T cells.
    • The IL-2 receptor is a three-chain molecule, and its expression is increased on activated T cells.

    Clonal Expansion

    • T lymphocytes activated by antigen and costimulation begin to proliferate, resulting in the expansion of antigen-specific clones.
    • The magnitude of clonal expansion is remarkable, especially for CD8+ T cells.
    • The expansion of CD4+ T cells is 100- to 1000-fold less than that of CD8+ cells.

    Differentiation of Naive T Cells into Effector Cells

    • Some of the progeny of antigen-stimulated, proliferating T cells differentiate into effector cells whose function is to eradicate infections.
    • Effector cells of the CD4+ lineage acquire the capacity to produce different sets of cytokines.
    • Effector cells of the CD8+ lineage acquire the ability to kill infected cells.

    Development of Memory T Lymphocytes

    • A fraction of antigen-activated T lymphocytes differentiates into long-lived memory cells.
    • Memory cells survive even after the infection is eradicated and antigen is no longer present.
    • Memory cells can be found in lymphoid organs, peripheral tissues, and the circulation.

    Migration of T Lymphocytes in Cell-Mediated Immune Reactions

    • T cells at different stages of their lives have to migrate in different ways.
    • Naive T cells migrate between blood and secondary lymphoid organs through HEVs (high endothelial venules).
    • HEVs are lined by specialized endothelial cells that express carbohydrate ligands that bind to L-selectin.### Migration of Naive T Cells
    • Naive T cells migrate through blood vessels in a multistep sequence similar to other leukocytes
    • Engagement of L-selectin with HEV (high endothelial venules) allows chemokines to bind to CCR7 on T cells
    • CCR7 transduces signals that activate LFA-1 (leukocyte function-associated antigen 1) on naive T cells, increasing binding affinity for ICAM-1 on HEV
    • Firm adhesion and arrest of rolling T cells occurs, followed by exit into the T cell zone of the lymph node

    Egress of T Cells from Lymph Nodes

    • Sphingosine 1-phosphate (S1P) plays a key role in T cell egress from lymph nodes
    • S1P levels are higher in blood and lymph than inside lymph nodes
    • S1P binds to its receptor, reducing expression on circulating naive T cells
    • When a naive T cell enters a node, S1P receptor expression increases, and the cell exits the node through efferent lymphatic vessels following the S1P gradient

    Activation and Differentiation of T Cells

    • Activated T cells do not express CCR7 or L-selectin, preventing re-entry into lymph nodes
    • Effector T cells migrate to sites of infection, expressing adhesion molecules and chemokine receptors that bind to ligands on vascular endothelium
    • Naive T cells do not express ligands for E- or P-selectin or receptors for chemokines produced at inflammatory sites, preventing migration into sites of infection

    Site-Specific Immune Response

    • Homing of effector T cells to a site of infection is independent of antigen recognition, but lymphocytes that recognize antigens are preferentially retained and activated at the site
    • Chemokines produced by macrophages and endothelial cells stimulate motility of transmigrating T cells
    • Effector T cells that leave the circulation and recognize microbial antigens presented by local tissue APCs become reactivated and contribute to killing microbes

    Decline of the Immune Response

    • After an infection is cleared, the immune response subsides, and the system returns to homeostasis
    • Survival and proliferation of T cells are maintained by antigen, costimulatory signals from CD28, and cytokines like IL-2
    • Once the infection is cleared, stimulated T cells die by apoptosis, and the response subsides within 1-2 weeks

    T Lymphocytes and Cell-Mediated Immunity

    • T lymphocytes perform multiple functions in defending against infections by various kinds of microbes.
    • They play a major role in cell-mediated immunity, which provides defense against infections by intracellular microbes.
    • Cell-mediated immunity is necessary to eliminate infections that occur inside cells, such as those caused by viruses and some bacteria.

    Phases of T Cell Responses

    • Naive T lymphocytes recognize antigens in peripheral lymphoid organs, which initiates proliferation and differentiation into effector and memory cells.
    • Effector cells perform their functions when they are activated by the same antigens in peripheral tissues or lymphoid organs.
    • The responses of naive T lymphocytes to cell-associated microbial antigens consist of a series of sequential steps, including:
      • Antigen recognition
      • Cytokine secretion and receptor expression
      • Clonal expansion
      • Differentiation into effector and memory cells

    Antigen Recognition and Costimulation

    • The initiation of T cell responses requires multiple receptors on the T cells recognizing ligands on antigen-presenting cells (APCs).
    • The T cell receptor (TCR) recognizes MHC-associated peptide antigens.
    • CD4 or CD8 coreceptors on the T cells recognize MHC molecules on the APC and help the TCR complex to deliver activating signals.
    • Adhesion molecules strengthen the binding of T cells to APCs.
    • Costimulators, such as B7-1 and B7-2, on APCs promote the responses of T cells to antigens.
    • Cytokines amplify the T cell response and direct it along various differentiation pathways.

    Role of Adhesion Molecules and Costimulation

    • Adhesion molecules, such as integrins, on T cells recognize ligands on APCs and stabilize the binding of T cells to APCs.
    • The binding of T cells to APCs must be stabilized for a sufficiently long period to achieve the necessary signaling threshold.
    • Costimulation ensures that naive T lymphocytes are activated fully by microbial antigens and not by harmless foreign substances or self-antigens.

    Inhibitory Receptors of T Cells

    • Inhibitory receptors, such as CTLA-4 and PD-1, are critical for limiting and terminating immune responses.
    • These receptors function to terminate responses of activated T cells and prevent immune responses against self-antigens.
    • Genetic deletion or blockade of these molecules can result in systemic autoimmune disease.

    Stimuli for Activation of CD8+ T Cells

    • The activation of CD8+ T cells is stimulated by recognition of class I MHC-associated peptides and requires costimulation and helper T cells.
    • The initiation of CD8+ T cell activation often requires cytosolic antigen from one cell (e.g., virus-infected or tumor cells) to be cross-presented by dendritic cells.
    • The differentiation of naive CD8+ T cells into fully active cytotoxic T lymphocytes (CTLs) and memory cells may require the concomitant activation of CD4+ helper T cells.### Helper T Cells and CD8+ T Cells
    • Human immunodeficiency virus (HIV) kills CD4+ but not CD8+ T cells, which is likely the explanation for the defective CTL responses to many viruses in HIV patients.
    • CD8+ T cells can respond to some viruses without the help of CD4+ T cells.

    Biochemical Pathways of T Cell Activation

    • T cell activation leads to protein synthesis, differentiation, and effector functions.
    • Antigen recognition triggers several biochemical mechanisms, including:
      • Kinase activation
      • Adaptor protein recruitment
      • Production of active transcription factors
    • The TCR complex, CD4/CD8 coreceptors, and CD28 coalesce at the center of the immune synapse, while integrins move to the periphery.
    • The immune synapse is required for optimal induction of activating signals in the T cell.

    Signaling Pathways

    • CD4 and CD8 coreceptors facilitate signaling through the protein tyrosine kinase Lck.
    • Lck phosphorylates ITAMs (immunoreceptor tyrosine-based activation motifs) in the CD3 and ζ chains.
    • The phosphorylated ITAMs in the ζ chain become docking sites for the tyrosine kinase ZAP-70.
    • ZAP-70 phosphorylates various adaptor proteins and enzymes, leading to additional signaling events.
    • The major signaling pathways linked to ζ-chain phosphorylation and ZAP-70 are:
      • Calcium-NFAT pathway
      • Ras- and Rac-MAP kinase pathways
      • PKCθ-NF-κB pathway
      • PI-3 kinase pathway

    Calcium-NFAT Pathway

    • NFAT (nuclear factor of activated T cells) is a transcription factor that is present in an inactive form in the cytoplasm of resting T cells.
    • NFAT activation and nuclear translocation depend on the concentration of Ca2+ ions in the cytosol.
    • The signaling pathway is initiated by ZAP-70-mediated phosphorylation and activation of phospholipase Cγ (PLCγ).
    • PLCγ catalyzes the hydrolysis of PIP2, generating IP3, which binds to IP3 receptors on the ER membrane, stimulating the release of Ca2+ from the ER.

    Ras- and Rac-MAP Kinase Pathways

    • These pathways are initiated by ZAP-70-dependent phosphorylation and accumulation of adaptor proteins at the plasma membrane.
    • The pathways lead to the activation of distinct MAP kinases (ERK and JNK), which induce the expression of the transcription factor AP-1.

    PKCθ-NF-κB Pathway

    • PKCθ is activated by diacylglycerol, which is generated by PLC-mediated hydrolysis of membrane inositol lipids.
    • PKCθ acts through adaptor proteins recruited to the TCR complex to activate NF-κB.
    • NF-κB is released from its inhibitor IκB and moves to the nucleus, promoting the transcription of several genes.

    PI-3 Kinase Pathway

    • PI-3 kinase phosphorylates the membrane phospholipid PIP2 to generate PIP3.
    • PIP3 is required for the activation of Akt, which has many roles, including stimulating the expression of antiapoptotic proteins and promoting survival of antigen-stimulated T cells.

    T Cell Functional Responses

    • T cell activation leads to the secretion of cytokines, such as IL-2, which act on the T cells themselves and on other cells involved in immune defenses.
    • Cytokines are produced by effector T cells and serve diverse roles in host defense.
    • IL-2 is produced by activated CD4+ T cells and stimulates the survival and proliferation of T cells.
    • The IL-2 receptor is a three-chain molecule, and its expression is increased on activated T cells.

    Clonal Expansion

    • T lymphocytes activated by antigen and costimulation begin to proliferate, resulting in the expansion of antigen-specific clones.
    • The magnitude of clonal expansion is remarkable, especially for CD8+ T cells.
    • The expansion of CD4+ T cells is 100- to 1000-fold less than that of CD8+ cells.

    Differentiation of Naive T Cells into Effector Cells

    • Some of the progeny of antigen-stimulated, proliferating T cells differentiate into effector cells whose function is to eradicate infections.
    • Effector cells of the CD4+ lineage acquire the capacity to produce different sets of cytokines.
    • Effector cells of the CD8+ lineage acquire the ability to kill infected cells.

    Development of Memory T Lymphocytes

    • A fraction of antigen-activated T lymphocytes differentiates into long-lived memory cells.
    • Memory cells survive even after the infection is eradicated and antigen is no longer present.
    • Memory cells can be found in lymphoid organs, peripheral tissues, and the circulation.

    Migration of T Lymphocytes in Cell-Mediated Immune Reactions

    • T cells at different stages of their lives have to migrate in different ways.
    • Naive T cells migrate between blood and secondary lymphoid organs through HEVs (high endothelial venules).
    • HEVs are lined by specialized endothelial cells that express carbohydrate ligands that bind to L-selectin.### Migration of Naive T Cells
    • Naive T cells migrate through blood vessels in a multistep sequence similar to other leukocytes
    • Engagement of L-selectin with HEV (high endothelial venules) allows chemokines to bind to CCR7 on T cells
    • CCR7 transduces signals that activate LFA-1 (leukocyte function-associated antigen 1) on naive T cells, increasing binding affinity for ICAM-1 on HEV
    • Firm adhesion and arrest of rolling T cells occurs, followed by exit into the T cell zone of the lymph node

    Egress of T Cells from Lymph Nodes

    • Sphingosine 1-phosphate (S1P) plays a key role in T cell egress from lymph nodes
    • S1P levels are higher in blood and lymph than inside lymph nodes
    • S1P binds to its receptor, reducing expression on circulating naive T cells
    • When a naive T cell enters a node, S1P receptor expression increases, and the cell exits the node through efferent lymphatic vessels following the S1P gradient

    Activation and Differentiation of T Cells

    • Activated T cells do not express CCR7 or L-selectin, preventing re-entry into lymph nodes
    • Effector T cells migrate to sites of infection, expressing adhesion molecules and chemokine receptors that bind to ligands on vascular endothelium
    • Naive T cells do not express ligands for E- or P-selectin or receptors for chemokines produced at inflammatory sites, preventing migration into sites of infection

    Site-Specific Immune Response

    • Homing of effector T cells to a site of infection is independent of antigen recognition, but lymphocytes that recognize antigens are preferentially retained and activated at the site
    • Chemokines produced by macrophages and endothelial cells stimulate motility of transmigrating T cells
    • Effector T cells that leave the circulation and recognize microbial antigens presented by local tissue APCs become reactivated and contribute to killing microbes

    Decline of the Immune Response

    • After an infection is cleared, the immune response subsides, and the system returns to homeostasis
    • Survival and proliferation of T cells are maintained by antigen, costimulatory signals from CD28, and cytokines like IL-2
    • Once the infection is cleared, stimulated T cells die by apoptosis, and the response subsides within 1-2 weeks

    T Lymphocytes and Cell-Mediated Immunity

    • T lymphocytes perform multiple functions in defending against infections by various kinds of microbes.
    • They play a major role in cell-mediated immunity, which provides defense against infections by intracellular microbes.
    • Cell-mediated immunity is necessary to eliminate infections that occur inside cells, such as those caused by viruses and some bacteria.

    Phases of T Cell Responses

    • Naive T lymphocytes recognize antigens in peripheral lymphoid organs, which initiates proliferation and differentiation into effector and memory cells.
    • Effector cells perform their functions when they are activated by the same antigens in peripheral tissues or lymphoid organs.
    • The responses of naive T lymphocytes to cell-associated microbial antigens consist of a series of sequential steps, including:
      • Antigen recognition
      • Cytokine secretion and receptor expression
      • Clonal expansion
      • Differentiation into effector and memory cells

    Antigen Recognition and Costimulation

    • The initiation of T cell responses requires multiple receptors on the T cells recognizing ligands on antigen-presenting cells (APCs).
    • The T cell receptor (TCR) recognizes MHC-associated peptide antigens.
    • CD4 or CD8 coreceptors on the T cells recognize MHC molecules on the APC and help the TCR complex to deliver activating signals.
    • Adhesion molecules strengthen the binding of T cells to APCs.
    • Costimulators, such as B7-1 and B7-2, on APCs promote the responses of T cells to antigens.
    • Cytokines amplify the T cell response and direct it along various differentiation pathways.

    Role of Adhesion Molecules and Costimulation

    • Adhesion molecules, such as integrins, on T cells recognize ligands on APCs and stabilize the binding of T cells to APCs.
    • The binding of T cells to APCs must be stabilized for a sufficiently long period to achieve the necessary signaling threshold.
    • Costimulation ensures that naive T lymphocytes are activated fully by microbial antigens and not by harmless foreign substances or self-antigens.

    Inhibitory Receptors of T Cells

    • Inhibitory receptors, such as CTLA-4 and PD-1, are critical for limiting and terminating immune responses.
    • These receptors function to terminate responses of activated T cells and prevent immune responses against self-antigens.
    • Genetic deletion or blockade of these molecules can result in systemic autoimmune disease.

    Stimuli for Activation of CD8+ T Cells

    • The activation of CD8+ T cells is stimulated by recognition of class I MHC-associated peptides and requires costimulation and helper T cells.
    • The initiation of CD8+ T cell activation often requires cytosolic antigen from one cell (e.g., virus-infected or tumor cells) to be cross-presented by dendritic cells.
    • The differentiation of naive CD8+ T cells into fully active cytotoxic T lymphocytes (CTLs) and memory cells may require the concomitant activation of CD4+ helper T cells.### Helper T Cells and CD8+ T Cells
    • Human immunodeficiency virus (HIV) kills CD4+ but not CD8+ T cells, which is likely the explanation for the defective CTL responses to many viruses in HIV patients.
    • CD8+ T cells can respond to some viruses without the help of CD4+ T cells.

    Biochemical Pathways of T Cell Activation

    • T cell activation leads to protein synthesis, differentiation, and effector functions.
    • Antigen recognition triggers several biochemical mechanisms, including:
      • Kinase activation
      • Adaptor protein recruitment
      • Production of active transcription factors
    • The TCR complex, CD4/CD8 coreceptors, and CD28 coalesce at the center of the immune synapse, while integrins move to the periphery.
    • The immune synapse is required for optimal induction of activating signals in the T cell.

    Signaling Pathways

    • CD4 and CD8 coreceptors facilitate signaling through the protein tyrosine kinase Lck.
    • Lck phosphorylates ITAMs (immunoreceptor tyrosine-based activation motifs) in the CD3 and ζ chains.
    • The phosphorylated ITAMs in the ζ chain become docking sites for the tyrosine kinase ZAP-70.
    • ZAP-70 phosphorylates various adaptor proteins and enzymes, leading to additional signaling events.
    • The major signaling pathways linked to ζ-chain phosphorylation and ZAP-70 are:
      • Calcium-NFAT pathway
      • Ras- and Rac-MAP kinase pathways
      • PKCθ-NF-κB pathway
      • PI-3 kinase pathway

    Calcium-NFAT Pathway

    • NFAT (nuclear factor of activated T cells) is a transcription factor that is present in an inactive form in the cytoplasm of resting T cells.
    • NFAT activation and nuclear translocation depend on the concentration of Ca2+ ions in the cytosol.
    • The signaling pathway is initiated by ZAP-70-mediated phosphorylation and activation of phospholipase Cγ (PLCγ).
    • PLCγ catalyzes the hydrolysis of PIP2, generating IP3, which binds to IP3 receptors on the ER membrane, stimulating the release of Ca2+ from the ER.

    Ras- and Rac-MAP Kinase Pathways

    • These pathways are initiated by ZAP-70-dependent phosphorylation and accumulation of adaptor proteins at the plasma membrane.
    • The pathways lead to the activation of distinct MAP kinases (ERK and JNK), which induce the expression of the transcription factor AP-1.

    PKCθ-NF-κB Pathway

    • PKCθ is activated by diacylglycerol, which is generated by PLC-mediated hydrolysis of membrane inositol lipids.
    • PKCθ acts through adaptor proteins recruited to the TCR complex to activate NF-κB.
    • NF-κB is released from its inhibitor IκB and moves to the nucleus, promoting the transcription of several genes.

    PI-3 Kinase Pathway

    • PI-3 kinase phosphorylates the membrane phospholipid PIP2 to generate PIP3.
    • PIP3 is required for the activation of Akt, which has many roles, including stimulating the expression of antiapoptotic proteins and promoting survival of antigen-stimulated T cells.

    T Cell Functional Responses

    • T cell activation leads to the secretion of cytokines, such as IL-2, which act on the T cells themselves and on other cells involved in immune defenses.
    • Cytokines are produced by effector T cells and serve diverse roles in host defense.
    • IL-2 is produced by activated CD4+ T cells and stimulates the survival and proliferation of T cells.
    • The IL-2 receptor is a three-chain molecule, and its expression is increased on activated T cells.

    Clonal Expansion

    • T lymphocytes activated by antigen and costimulation begin to proliferate, resulting in the expansion of antigen-specific clones.
    • The magnitude of clonal expansion is remarkable, especially for CD8+ T cells.
    • The expansion of CD4+ T cells is 100- to 1000-fold less than that of CD8+ cells.

    Differentiation of Naive T Cells into Effector Cells

    • Some of the progeny of antigen-stimulated, proliferating T cells differentiate into effector cells whose function is to eradicate infections.
    • Effector cells of the CD4+ lineage acquire the capacity to produce different sets of cytokines.
    • Effector cells of the CD8+ lineage acquire the ability to kill infected cells.

    Development of Memory T Lymphocytes

    • A fraction of antigen-activated T lymphocytes differentiates into long-lived memory cells.
    • Memory cells survive even after the infection is eradicated and antigen is no longer present.
    • Memory cells can be found in lymphoid organs, peripheral tissues, and the circulation.

    Migration of T Lymphocytes in Cell-Mediated Immune Reactions

    • T cells at different stages of their lives have to migrate in different ways.
    • Naive T cells migrate between blood and secondary lymphoid organs through HEVs (high endothelial venules).
    • HEVs are lined by specialized endothelial cells that express carbohydrate ligands that bind to L-selectin.### Migration of Naive T Cells
    • Naive T cells migrate through blood vessels in a multistep sequence similar to other leukocytes
    • Engagement of L-selectin with HEV (high endothelial venules) allows chemokines to bind to CCR7 on T cells
    • CCR7 transduces signals that activate LFA-1 (leukocyte function-associated antigen 1) on naive T cells, increasing binding affinity for ICAM-1 on HEV
    • Firm adhesion and arrest of rolling T cells occurs, followed by exit into the T cell zone of the lymph node

    Egress of T Cells from Lymph Nodes

    • Sphingosine 1-phosphate (S1P) plays a key role in T cell egress from lymph nodes
    • S1P levels are higher in blood and lymph than inside lymph nodes
    • S1P binds to its receptor, reducing expression on circulating naive T cells
    • When a naive T cell enters a node, S1P receptor expression increases, and the cell exits the node through efferent lymphatic vessels following the S1P gradient

    Activation and Differentiation of T Cells

    • Activated T cells do not express CCR7 or L-selectin, preventing re-entry into lymph nodes
    • Effector T cells migrate to sites of infection, expressing adhesion molecules and chemokine receptors that bind to ligands on vascular endothelium
    • Naive T cells do not express ligands for E- or P-selectin or receptors for chemokines produced at inflammatory sites, preventing migration into sites of infection

    Site-Specific Immune Response

    • Homing of effector T cells to a site of infection is independent of antigen recognition, but lymphocytes that recognize antigens are preferentially retained and activated at the site
    • Chemokines produced by macrophages and endothelial cells stimulate motility of transmigrating T cells
    • Effector T cells that leave the circulation and recognize microbial antigens presented by local tissue APCs become reactivated and contribute to killing microbes

    Decline of the Immune Response

    • After an infection is cleared, the immune response subsides, and the system returns to homeostasis
    • Survival and proliferation of T cells are maintained by antigen, costimulatory signals from CD28, and cytokines like IL-2
    • Once the infection is cleared, stimulated T cells die by apoptosis, and the response subsides within 1-2 weeks

    T Lymphocytes and Cell-Mediated Immunity

    • T lymphocytes perform multiple functions in defending against infections by various kinds of microbes.
    • They play a major role in cell-mediated immunity, which provides defense against infections by intracellular microbes.
    • Cell-mediated immunity is necessary to eliminate infections that occur inside cells, such as those caused by viruses and some bacteria.

    Phases of T Cell Responses

    • Naive T lymphocytes recognize antigens in peripheral lymphoid organs, which initiates proliferation and differentiation into effector and memory cells.
    • Effector cells perform their functions when they are activated by the same antigens in peripheral tissues or lymphoid organs.
    • The responses of naive T lymphocytes to cell-associated microbial antigens consist of a series of sequential steps, including:
      • Antigen recognition
      • Cytokine secretion and receptor expression
      • Clonal expansion
      • Differentiation into effector and memory cells

    Antigen Recognition and Costimulation

    • The initiation of T cell responses requires multiple receptors on the T cells recognizing ligands on antigen-presenting cells (APCs).
    • The T cell receptor (TCR) recognizes MHC-associated peptide antigens.
    • CD4 or CD8 coreceptors on the T cells recognize MHC molecules on the APC and help the TCR complex to deliver activating signals.
    • Adhesion molecules strengthen the binding of T cells to APCs.
    • Costimulators, such as B7-1 and B7-2, on APCs promote the responses of T cells to antigens.
    • Cytokines amplify the T cell response and direct it along various differentiation pathways.

    Role of Adhesion Molecules and Costimulation

    • Adhesion molecules, such as integrins, on T cells recognize ligands on APCs and stabilize the binding of T cells to APCs.
    • The binding of T cells to APCs must be stabilized for a sufficiently long period to achieve the necessary signaling threshold.
    • Costimulation ensures that naive T lymphocytes are activated fully by microbial antigens and not by harmless foreign substances or self-antigens.

    Inhibitory Receptors of T Cells

    • Inhibitory receptors, such as CTLA-4 and PD-1, are critical for limiting and terminating immune responses.
    • These receptors function to terminate responses of activated T cells and prevent immune responses against self-antigens.
    • Genetic deletion or blockade of these molecules can result in systemic autoimmune disease.

    Stimuli for Activation of CD8+ T Cells

    • The activation of CD8+ T cells is stimulated by recognition of class I MHC-associated peptides and requires costimulation and helper T cells.
    • The initiation of CD8+ T cell activation often requires cytosolic antigen from one cell (e.g., virus-infected or tumor cells) to be cross-presented by dendritic cells.
    • The differentiation of naive CD8+ T cells into fully active cytotoxic T lymphocytes (CTLs) and memory cells may require the concomitant activation of CD4+ helper T cells.### Helper T Cells and CD8+ T Cells
    • Human immunodeficiency virus (HIV) kills CD4+ but not CD8+ T cells, which is likely the explanation for the defective CTL responses to many viruses in HIV patients.
    • CD8+ T cells can respond to some viruses without the help of CD4+ T cells.

    Biochemical Pathways of T Cell Activation

    • T cell activation leads to protein synthesis, differentiation, and effector functions.
    • Antigen recognition triggers several biochemical mechanisms, including:
      • Kinase activation
      • Adaptor protein recruitment
      • Production of active transcription factors
    • The TCR complex, CD4/CD8 coreceptors, and CD28 coalesce at the center of the immune synapse, while integrins move to the periphery.
    • The immune synapse is required for optimal induction of activating signals in the T cell.

    Signaling Pathways

    • CD4 and CD8 coreceptors facilitate signaling through the protein tyrosine kinase Lck.
    • Lck phosphorylates ITAMs (immunoreceptor tyrosine-based activation motifs) in the CD3 and ζ chains.
    • The phosphorylated ITAMs in the ζ chain become docking sites for the tyrosine kinase ZAP-70.
    • ZAP-70 phosphorylates various adaptor proteins and enzymes, leading to additional signaling events.
    • The major signaling pathways linked to ζ-chain phosphorylation and ZAP-70 are:
      • Calcium-NFAT pathway
      • Ras- and Rac-MAP kinase pathways
      • PKCθ-NF-κB pathway
      • PI-3 kinase pathway

    Calcium-NFAT Pathway

    • NFAT (nuclear factor of activated T cells) is a transcription factor that is present in an inactive form in the cytoplasm of resting T cells.
    • NFAT activation and nuclear translocation depend on the concentration of Ca2+ ions in the cytosol.
    • The signaling pathway is initiated by ZAP-70-mediated phosphorylation and activation of phospholipase Cγ (PLCγ).
    • PLCγ catalyzes the hydrolysis of PIP2, generating IP3, which binds to IP3 receptors on the ER membrane, stimulating the release of Ca2+ from the ER.

    Ras- and Rac-MAP Kinase Pathways

    • These pathways are initiated by ZAP-70-dependent phosphorylation and accumulation of adaptor proteins at the plasma membrane.
    • The pathways lead to the activation of distinct MAP kinases (ERK and JNK), which induce the expression of the transcription factor AP-1.

    PKCθ-NF-κB Pathway

    • PKCθ is activated by diacylglycerol, which is generated by PLC-mediated hydrolysis of membrane inositol lipids.
    • PKCθ acts through adaptor proteins recruited to the TCR complex to activate NF-κB.
    • NF-κB is released from its inhibitor IκB and moves to the nucleus, promoting the transcription of several genes.

    PI-3 Kinase Pathway

    • PI-3 kinase phosphorylates the membrane phospholipid PIP2 to generate PIP3.
    • PIP3 is required for the activation of Akt, which has many roles, including stimulating the expression of antiapoptotic proteins and promoting survival of antigen-stimulated T cells.

    T Cell Functional Responses

    • T cell activation leads to the secretion of cytokines, such as IL-2, which act on the T cells themselves and on other cells involved in immune defenses.
    • Cytokines are produced by effector T cells and serve diverse roles in host defense.
    • IL-2 is produced by activated CD4+ T cells and stimulates the survival and proliferation of T cells.
    • The IL-2 receptor is a three-chain molecule, and its expression is increased on activated T cells.

    Clonal Expansion

    • T lymphocytes activated by antigen and costimulation begin to proliferate, resulting in the expansion of antigen-specific clones.
    • The magnitude of clonal expansion is remarkable, especially for CD8+ T cells.
    • The expansion of CD4+ T cells is 100- to 1000-fold less than that of CD8+ cells.

    Differentiation of Naive T Cells into Effector Cells

    • Some of the progeny of antigen-stimulated, proliferating T cells differentiate into effector cells whose function is to eradicate infections.
    • Effector cells of the CD4+ lineage acquire the capacity to produce different sets of cytokines.
    • Effector cells of the CD8+ lineage acquire the ability to kill infected cells.

    Development of Memory T Lymphocytes

    • A fraction of antigen-activated T lymphocytes differentiates into long-lived memory cells.
    • Memory cells survive even after the infection is eradicated and antigen is no longer present.
    • Memory cells can be found in lymphoid organs, peripheral tissues, and the circulation.

    Migration of T Lymphocytes in Cell-Mediated Immune Reactions

    • T cells at different stages of their lives have to migrate in different ways.
    • Naive T cells migrate between blood and secondary lymphoid organs through HEVs (high endothelial venules).
    • HEVs are lined by specialized endothelial cells that express carbohydrate ligands that bind to L-selectin.### Migration of Naive T Cells
    • Naive T cells migrate through blood vessels in a multistep sequence similar to other leukocytes
    • Engagement of L-selectin with HEV (high endothelial venules) allows chemokines to bind to CCR7 on T cells
    • CCR7 transduces signals that activate LFA-1 (leukocyte function-associated antigen 1) on naive T cells, increasing binding affinity for ICAM-1 on HEV
    • Firm adhesion and arrest of rolling T cells occurs, followed by exit into the T cell zone of the lymph node

    Egress of T Cells from Lymph Nodes

    • Sphingosine 1-phosphate (S1P) plays a key role in T cell egress from lymph nodes
    • S1P levels are higher in blood and lymph than inside lymph nodes
    • S1P binds to its receptor, reducing expression on circulating naive T cells
    • When a naive T cell enters a node, S1P receptor expression increases, and the cell exits the node through efferent lymphatic vessels following the S1P gradient

    Activation and Differentiation of T Cells

    • Activated T cells do not express CCR7 or L-selectin, preventing re-entry into lymph nodes
    • Effector T cells migrate to sites of infection, expressing adhesion molecules and chemokine receptors that bind to ligands on vascular endothelium
    • Naive T cells do not express ligands for E- or P-selectin or receptors for chemokines produced at inflammatory sites, preventing migration into sites of infection

    Site-Specific Immune Response

    • Homing of effector T cells to a site of infection is independent of antigen recognition, but lymphocytes that recognize antigens are preferentially retained and activated at the site
    • Chemokines produced by macrophages and endothelial cells stimulate motility of transmigrating T cells
    • Effector T cells that leave the circulation and recognize microbial antigens presented by local tissue APCs become reactivated and contribute to killing microbes

    Decline of the Immune Response

    • After an infection is cleared, the immune response subsides, and the system returns to homeostasis
    • Survival and proliferation of T cells are maintained by antigen, costimulatory signals from CD28, and cytokines like IL-2
    • Once the infection is cleared, stimulated T cells die by apoptosis, and the response subsides within 1-2 weeks

    T Lymphocytes and Cell-Mediated Immunity

    • T lymphocytes perform multiple functions in defending against infections by various kinds of microbes.
    • They play a major role in cell-mediated immunity, which provides defense against infections by intracellular microbes.
    • Cell-mediated immunity is necessary to eliminate infections that occur inside cells, such as those caused by viruses and some bacteria.

    Phases of T Cell Responses

    • Naive T lymphocytes recognize antigens in peripheral lymphoid organs, which initiates proliferation and differentiation into effector and memory cells.
    • Effector cells perform their functions when they are activated by the same antigens in peripheral tissues or lymphoid organs.
    • The responses of naive T lymphocytes to cell-associated microbial antigens consist of a series of sequential steps, including:
      • Antigen recognition
      • Cytokine secretion and receptor expression
      • Clonal expansion
      • Differentiation into effector and memory cells

    Antigen Recognition and Costimulation

    • The initiation of T cell responses requires multiple receptors on the T cells recognizing ligands on antigen-presenting cells (APCs).
    • The T cell receptor (TCR) recognizes MHC-associated peptide antigens.
    • CD4 or CD8 coreceptors on the T cells recognize MHC molecules on the APC and help the TCR complex to deliver activating signals.
    • Adhesion molecules strengthen the binding of T cells to APCs.
    • Costimulators, such as B7-1 and B7-2, on APCs promote the responses of T cells to antigens.
    • Cytokines amplify the T cell response and direct it along various differentiation pathways.

    Role of Adhesion Molecules and Costimulation

    • Adhesion molecules, such as integrins, on T cells recognize ligands on APCs and stabilize the binding of T cells to APCs.
    • The binding of T cells to APCs must be stabilized for a sufficiently long period to achieve the necessary signaling threshold.
    • Costimulation ensures that naive T lymphocytes are activated fully by microbial antigens and not by harmless foreign substances or self-antigens.

    Inhibitory Receptors of T Cells

    • Inhibitory receptors, such as CTLA-4 and PD-1, are critical for limiting and terminating immune responses.
    • These receptors function to terminate responses of activated T cells and prevent immune responses against self-antigens.
    • Genetic deletion or blockade of these molecules can result in systemic autoimmune disease.

    Stimuli for Activation of CD8+ T Cells

    • The activation of CD8+ T cells is stimulated by recognition of class I MHC-associated peptides and requires costimulation and helper T cells.
    • The initiation of CD8+ T cell activation often requires cytosolic antigen from one cell (e.g., virus-infected or tumor cells) to be cross-presented by dendritic cells.
    • The differentiation of naive CD8+ T cells into fully active cytotoxic T lymphocytes (CTLs) and memory cells may require the concomitant activation of CD4+ helper T cells.### Helper T Cells and CD8+ T Cells
    • Human immunodeficiency virus (HIV) kills CD4+ but not CD8+ T cells, which is likely the explanation for the defective CTL responses to many viruses in HIV patients.
    • CD8+ T cells can respond to some viruses without the help of CD4+ T cells.

    Biochemical Pathways of T Cell Activation

    • T cell activation leads to protein synthesis, differentiation, and effector functions.
    • Antigen recognition triggers several biochemical mechanisms, including:
      • Kinase activation
      • Adaptor protein recruitment
      • Production of active transcription factors
    • The TCR complex, CD4/CD8 coreceptors, and CD28 coalesce at the center of the immune synapse, while integrins move to the periphery.
    • The immune synapse is required for optimal induction of activating signals in the T cell.

    Signaling Pathways

    • CD4 and CD8 coreceptors facilitate signaling through the protein tyrosine kinase Lck.
    • Lck phosphorylates ITAMs (immunoreceptor tyrosine-based activation motifs) in the CD3 and ζ chains.
    • The phosphorylated ITAMs in the ζ chain become docking sites for the tyrosine kinase ZAP-70.
    • ZAP-70 phosphorylates various adaptor proteins and enzymes, leading to additional signaling events.
    • The major signaling pathways linked to ζ-chain phosphorylation and ZAP-70 are:
      • Calcium-NFAT pathway
      • Ras- and Rac-MAP kinase pathways
      • PKCθ-NF-κB pathway
      • PI-3 kinase pathway

    Calcium-NFAT Pathway

    • NFAT (nuclear factor of activated T cells) is a transcription factor that is present in an inactive form in the cytoplasm of resting T cells.
    • NFAT activation and nuclear translocation depend on the concentration of Ca2+ ions in the cytosol.
    • The signaling pathway is initiated by ZAP-70-mediated phosphorylation and activation of phospholipase Cγ (PLCγ).
    • PLCγ catalyzes the hydrolysis of PIP2, generating IP3, which binds to IP3 receptors on the ER membrane, stimulating the release of Ca2+ from the ER.

    Ras- and Rac-MAP Kinase Pathways

    • These pathways are initiated by ZAP-70-dependent phosphorylation and accumulation of adaptor proteins at the plasma membrane.
    • The pathways lead to the activation of distinct MAP kinases (ERK and JNK), which induce the expression of the transcription factor AP-1.

    PKCθ-NF-κB Pathway

    • PKCθ is activated by diacylglycerol, which is generated by PLC-mediated hydrolysis of membrane inositol lipids.
    • PKCθ acts through adaptor proteins recruited to the TCR complex to activate NF-κB.
    • NF-κB is released from its inhibitor IκB and moves to the nucleus, promoting the transcription of several genes.

    PI-3 Kinase Pathway

    • PI-3 kinase phosphorylates the membrane phospholipid PIP2 to generate PIP3.
    • PIP3 is required for the activation of Akt, which has many roles, including stimulating the expression of antiapoptotic proteins and promoting survival of antigen-stimulated T cells.

    T Cell Functional Responses

    • T cell activation leads to the secretion of cytokines, such as IL-2, which act on the T cells themselves and on other cells involved in immune defenses.
    • Cytokines are produced by effector T cells and serve diverse roles in host defense.
    • IL-2 is produced by activated CD4+ T cells and stimulates the survival and proliferation of T cells.
    • The IL-2 receptor is a three-chain molecule, and its expression is increased on activated T cells.

    Clonal Expansion

    • T lymphocytes activated by antigen and costimulation begin to proliferate, resulting in the expansion of antigen-specific clones.
    • The magnitude of clonal expansion is remarkable, especially for CD8+ T cells.
    • The expansion of CD4+ T cells is 100- to 1000-fold less than that of CD8+ cells.

    Differentiation of Naive T Cells into Effector Cells

    • Some of the progeny of antigen-stimulated, proliferating T cells differentiate into effector cells whose function is to eradicate infections.
    • Effector cells of the CD4+ lineage acquire the capacity to produce different sets of cytokines.
    • Effector cells of the CD8+ lineage acquire the ability to kill infected cells.

    Development of Memory T Lymphocytes

    • A fraction of antigen-activated T lymphocytes differentiates into long-lived memory cells.
    • Memory cells survive even after the infection is eradicated and antigen is no longer present.
    • Memory cells can be found in lymphoid organs, peripheral tissues, and the circulation.

    Migration of T Lymphocytes in Cell-Mediated Immune Reactions

    • T cells at different stages of their lives have to migrate in different ways.
    • Naive T cells migrate between blood and secondary lymphoid organs through HEVs (high endothelial venules).
    • HEVs are lined by specialized endothelial cells that express carbohydrate ligands that bind to L-selectin.### Migration of Naive T Cells
    • Naive T cells migrate through blood vessels in a multistep sequence similar to other leukocytes
    • Engagement of L-selectin with HEV (high endothelial venules) allows chemokines to bind to CCR7 on T cells
    • CCR7 transduces signals that activate LFA-1 (leukocyte function-associated antigen 1) on naive T cells, increasing binding affinity for ICAM-1 on HEV
    • Firm adhesion and arrest of rolling T cells occurs, followed by exit into the T cell zone of the lymph node

    Egress of T Cells from Lymph Nodes

    • Sphingosine 1-phosphate (S1P) plays a key role in T cell egress from lymph nodes
    • S1P levels are higher in blood and lymph than inside lymph nodes
    • S1P binds to its receptor, reducing expression on circulating naive T cells
    • When a naive T cell enters a node, S1P receptor expression increases, and the cell exits the node through efferent lymphatic vessels following the S1P gradient

    Activation and Differentiation of T Cells

    • Activated T cells do not express CCR7 or L-selectin, preventing re-entry into lymph nodes
    • Effector T cells migrate to sites of infection, expressing adhesion molecules and chemokine receptors that bind to ligands on vascular endothelium
    • Naive T cells do not express ligands for E- or P-selectin or receptors for chemokines produced at inflammatory sites, preventing migration into sites of infection

    Site-Specific Immune Response

    • Homing of effector T cells to a site of infection is independent of antigen recognition, but lymphocytes that recognize antigens are preferentially retained and activated at the site
    • Chemokines produced by macrophages and endothelial cells stimulate motility of transmigrating T cells
    • Effector T cells that leave the circulation and recognize microbial antigens presented by local tissue APCs become reactivated and contribute to killing microbes

    Decline of the Immune Response

    • After an infection is cleared, the immune response subsides, and the system returns to homeostasis
    • Survival and proliferation of T cells are maintained by antigen, costimulatory signals from CD28, and cytokines like IL-2
    • Once the infection is cleared, stimulated T cells die by apoptosis, and the response subsides within 1-2 weeks

    T Lymphocytes and Cell-Mediated Immunity

    • T lymphocytes perform multiple functions in defending against infections by various kinds of microbes.
    • They play a major role in cell-mediated immunity, which provides defense against infections by intracellular microbes.
    • Cell-mediated immunity is necessary to eliminate infections that occur inside cells, such as those caused by viruses and some bacteria.

    Phases of T Cell Responses

    • Naive T lymphocytes recognize antigens in peripheral lymphoid organs, which initiates proliferation and differentiation into effector and memory cells.
    • Effector cells perform their functions when they are activated by the same antigens in peripheral tissues or lymphoid organs.
    • The responses of naive T lymphocytes to cell-associated microbial antigens consist of a series of sequential steps, including:
      • Antigen recognition
      • Cytokine secretion and receptor expression
      • Clonal expansion
      • Differentiation into effector and memory cells

    Antigen Recognition and Costimulation

    • The initiation of T cell responses requires multiple receptors on the T cells recognizing ligands on antigen-presenting cells (APCs).
    • The T cell receptor (TCR) recognizes MHC-associated peptide antigens.
    • CD4 or CD8 coreceptors on the T cells recognize MHC molecules on the APC and help the TCR complex to deliver activating signals.
    • Adhesion molecules strengthen the binding of T cells to APCs.
    • Costimulators, such as B7-1 and B7-2, on APCs promote the responses of T cells to antigens.
    • Cytokines amplify the T cell response and direct it along various differentiation pathways.

    Role of Adhesion Molecules and Costimulation

    • Adhesion molecules, such as integrins, on T cells recognize ligands on APCs and stabilize the binding of T cells to APCs.
    • The binding of T cells to APCs must be stabilized for a sufficiently long period to achieve the necessary signaling threshold.
    • Costimulation ensures that naive T lymphocytes are activated fully by microbial antigens and not by harmless foreign substances or self-antigens.

    Inhibitory Receptors of T Cells

    • Inhibitory receptors, such as CTLA-4 and PD-1, are critical for limiting and terminating immune responses.
    • These receptors function to terminate responses of activated T cells and prevent immune responses against self-antigens.
    • Genetic deletion or blockade of these molecules can result in systemic autoimmune disease.

    Stimuli for Activation of CD8+ T Cells

    • The activation of CD8+ T cells is stimulated by recognition of class I MHC-associated peptides and requires costimulation and helper T cells.
    • The initiation of CD8+ T cell activation often requires cytosolic antigen from one cell (e.g., virus-infected or tumor cells) to be cross-presented by dendritic cells.
    • The differentiation of naive CD8+ T cells into fully active cytotoxic T lymphocytes (CTLs) and memory cells may require the concomitant activation of CD4+ helper T cells.### Helper T Cells and CD8+ T Cells
    • Human immunodeficiency virus (HIV) kills CD4+ but not CD8+ T cells, which is likely the explanation for the defective CTL responses to many viruses in HIV patients.
    • CD8+ T cells can respond to some viruses without the help of CD4+ T cells.

    Biochemical Pathways of T Cell Activation

    • T cell activation leads to protein synthesis, differentiation, and effector functions.
    • Antigen recognition triggers several biochemical mechanisms, including:
      • Kinase activation
      • Adaptor protein recruitment
      • Production of active transcription factors
    • The TCR complex, CD4/CD8 coreceptors, and CD28 coalesce at the center of the immune synapse, while integrins move to the periphery.
    • The immune synapse is required for optimal induction of activating signals in the T cell.

    Signaling Pathways

    • CD4 and CD8 coreceptors facilitate signaling through the protein tyrosine kinase Lck.
    • Lck phosphorylates ITAMs (immunoreceptor tyrosine-based activation motifs) in the CD3 and ζ chains.
    • The phosphorylated ITAMs in the ζ chain become docking sites for the tyrosine kinase ZAP-70.
    • ZAP-70 phosphorylates various adaptor proteins and enzymes, leading to additional signaling events.
    • The major signaling pathways linked to ζ-chain phosphorylation and ZAP-70 are:
      • Calcium-NFAT pathway
      • Ras- and Rac-MAP kinase pathways
      • PKCθ-NF-κB pathway
      • PI-3 kinase pathway

    Calcium-NFAT Pathway

    • NFAT (nuclear factor of activated T cells) is a transcription factor that is present in an inactive form in the cytoplasm of resting T cells.
    • NFAT activation and nuclear translocation depend on the concentration of Ca2+ ions in the cytosol.
    • The signaling pathway is initiated by ZAP-70-mediated phosphorylation and activation of phospholipase Cγ (PLCγ).
    • PLCγ catalyzes the hydrolysis of PIP2, generating IP3, which binds to IP3 receptors on the ER membrane, stimulating the release of Ca2+ from the ER.

    Ras- and Rac-MAP Kinase Pathways

    • These pathways are initiated by ZAP-70-dependent phosphorylation and accumulation of adaptor proteins at the plasma membrane.
    • The pathways lead to the activation of distinct MAP kinases (ERK and JNK), which induce the expression of the transcription factor AP-1.

    PKCθ-NF-κB Pathway

    • PKCθ is activated by diacylglycerol, which is generated by PLC-mediated hydrolysis of membrane inositol lipids.
    • PKCθ acts through adaptor proteins recruited to the TCR complex to activate NF-κB.
    • NF-κB is released from its inhibitor IκB and moves to the nucleus, promoting the transcription of several genes.

    PI-3 Kinase Pathway

    • PI-3 kinase phosphorylates the membrane phospholipid PIP2 to generate PIP3.
    • PIP3 is required for the activation of Akt, which has many roles, including stimulating the expression of antiapoptotic proteins and promoting survival of antigen-stimulated T cells.

    T Cell Functional Responses

    • T cell activation leads to the secretion of cytokines, such as IL-2, which act on the T cells themselves and on other cells involved in immune defenses.
    • Cytokines are produced by effector T cells and serve diverse roles in host defense.
    • IL-2 is produced by activated CD4+ T cells and stimulates the survival and proliferation of T cells.
    • The IL-2 receptor is a three-chain molecule, and its expression is increased on activated T cells.

    Clonal Expansion

    • T lymphocytes activated by antigen and costimulation begin to proliferate, resulting in the expansion of antigen-specific clones.
    • The magnitude of clonal expansion is remarkable, especially for CD8+ T cells.
    • The expansion of CD4+ T cells is 100- to 1000-fold less than that of CD8+ cells.

    Differentiation of Naive T Cells into Effector Cells

    • Some of the progeny of antigen-stimulated, proliferating T cells differentiate into effector cells whose function is to eradicate infections.
    • Effector cells of the CD4+ lineage acquire the capacity to produce different sets of cytokines.
    • Effector cells of the CD8+ lineage acquire the ability to kill infected cells.

    Development of Memory T Lymphocytes

    • A fraction of antigen-activated T lymphocytes differentiates into long-lived memory cells.
    • Memory cells survive even after the infection is eradicated and antigen is no longer present.
    • Memory cells can be found in lymphoid organs, peripheral tissues, and the circulation.

    Migration of T Lymphocytes in Cell-Mediated Immune Reactions

    • T cells at different stages of their lives have to migrate in different ways.
    • Naive T cells migrate between blood and secondary lymphoid organs through HEVs (high endothelial venules).
    • HEVs are lined by specialized endothelial cells that express carbohydrate ligands that bind to L-selectin.### Migration of Naive T Cells
    • Naive T cells migrate through blood vessels in a multistep sequence similar to other leukocytes
    • Engagement of L-selectin with HEV (high endothelial venules) allows chemokines to bind to CCR7 on T cells
    • CCR7 transduces signals that activate LFA-1 (leukocyte function-associated antigen 1) on naive T cells, increasing binding affinity for ICAM-1 on HEV
    • Firm adhesion and arrest of rolling T cells occurs, followed by exit into the T cell zone of the lymph node

    Egress of T Cells from Lymph Nodes

    • Sphingosine 1-phosphate (S1P) plays a key role in T cell egress from lymph nodes
    • S1P levels are higher in blood and lymph than inside lymph nodes
    • S1P binds to its receptor, reducing expression on circulating naive T cells
    • When a naive T cell enters a node, S1P receptor expression increases, and the cell exits the node through efferent lymphatic vessels following the S1P gradient

    Activation and Differentiation of T Cells

    • Activated T cells do not express CCR7 or L-selectin, preventing re-entry into lymph nodes
    • Effector T cells migrate to sites of infection, expressing adhesion molecules and chemokine receptors that bind to ligands on vascular endothelium
    • Naive T cells do not express ligands for E- or P-selectin or receptors for chemokines produced at inflammatory sites, preventing migration into sites of infection

    Site-Specific Immune Response

    • Homing of effector T cells to a site of infection is independent of antigen recognition, but lymphocytes that recognize antigens are preferentially retained and activated at the site
    • Chemokines produced by macrophages and endothelial cells stimulate motility of transmigrating T cells
    • Effector T cells that leave the circulation and recognize microbial antigens presented by local tissue APCs become reactivated and contribute to killing microbes

    Decline of the Immune Response

    • After an infection is cleared, the immune response subsides, and the system returns to homeostasis
    • Survival and proliferation of T cells are maintained by antigen, costimulatory signals from CD28, and cytokines like IL-2
    • Once the infection is cleared, stimulated T cells die by apoptosis, and the response subsides within 1-2 weeks

    T Lymphocytes and Cell-Mediated Immunity

    • T lymphocytes perform multiple functions in defending against infections by various kinds of microbes.
    • They play a major role in cell-mediated immunity, which provides defense against infections by intracellular microbes.
    • Cell-mediated immunity is necessary to eliminate infections that occur inside cells, such as those caused by viruses and some bacteria.

    Phases of T Cell Responses

    • Naive T lymphocytes recognize antigens in peripheral lymphoid organs, which initiates proliferation and differentiation into effector and memory cells.
    • Effector cells perform their functions when they are activated by the same antigens in peripheral tissues or lymphoid organs.
    • The responses of naive T lymphocytes to cell-associated microbial antigens consist of a series of sequential steps, including:
      • Antigen recognition
      • Cytokine secretion and receptor expression
      • Clonal expansion
      • Differentiation into effector and memory cells

    Antigen Recognition and Costimulation

    • The initiation of T cell responses requires multiple receptors on the T cells recognizing ligands on antigen-presenting cells (APCs).
    • The T cell receptor (TCR) recognizes MHC-associated peptide antigens.
    • CD4 or CD8 coreceptors on the T cells recognize MHC molecules on the APC and help the TCR complex to deliver activating signals.
    • Adhesion molecules strengthen the binding of T cells to APCs.
    • Costimulators, such as B7-1 and B7-2, on APCs promote the responses of T cells to antigens.
    • Cytokines amplify the T cell response and direct it along various differentiation pathways.

    Role of Adhesion Molecules and Costimulation

    • Adhesion molecules, such as integrins, on T cells recognize ligands on APCs and stabilize the binding of T cells to APCs.
    • The binding of T cells to APCs must be stabilized for a sufficiently long period to achieve the necessary signaling threshold.
    • Costimulation ensures that naive T lymphocytes are activated fully by microbial antigens and not by harmless foreign substances or self-antigens.

    Inhibitory Receptors of T Cells

    • Inhibitory receptors, such as CTLA-4 and PD-1, are critical for limiting and terminating immune responses.
    • These receptors function to terminate responses of activated T cells and prevent immune responses against self-antigens.
    • Genetic deletion or blockade of these molecules can result in systemic autoimmune disease.

    Stimuli for Activation of CD8+ T Cells

    • The activation of CD8+ T cells is stimulated by recognition of class I MHC-associated peptides and requires costimulation and helper T cells.
    • The initiation of CD8+ T cell activation often requires cytosolic antigen from one cell (e.g., virus-infected or tumor cells) to be cross-presented by dendritic cells.
    • The differentiation of naive CD8+ T cells into fully active cytotoxic T lymphocytes (CTLs) and memory cells may require the concomitant activation of CD4+ helper T cells.### Helper T Cells and CD8+ T Cells
    • Human immunodeficiency virus (HIV) kills CD4+ but not CD8+ T cells, which is likely the explanation for the defective CTL responses to many viruses in HIV patients.
    • CD8+ T cells can respond to some viruses without the help of CD4+ T cells.

    Biochemical Pathways of T Cell Activation

    • T cell activation leads to protein synthesis, differentiation, and effector functions.
    • Antigen recognition triggers several biochemical mechanisms, including:
      • Kinase activation
      • Adaptor protein recruitment
      • Production of active transcription factors
    • The TCR complex, CD4/CD8 coreceptors, and CD28 coalesce at the center of the immune synapse, while integrins move to the periphery.
    • The immune synapse is required for optimal induction of activating signals in the T cell.

    Signaling Pathways

    • CD4 and CD8 coreceptors facilitate signaling through the protein tyrosine kinase Lck.
    • Lck phosphorylates ITAMs (immunoreceptor tyrosine-based activation motifs) in the CD3 and ζ chains.
    • The phosphorylated ITAMs in the ζ chain become docking sites for the tyrosine kinase ZAP-70.
    • ZAP-70 phosphorylates various adaptor proteins and enzymes, leading to additional signaling events.
    • The major signaling pathways linked to ζ-chain phosphorylation and ZAP-70 are:
      • Calcium-NFAT pathway
      • Ras- and Rac-MAP kinase pathways
      • PKCθ-NF-κB pathway
      • PI-3 kinase pathway

    Calcium-NFAT Pathway

    • NFAT (nuclear factor of activated T cells) is a transcription factor that is present in an inactive form in the cytoplasm of resting T cells.
    • NFAT activation and nuclear translocation depend on the concentration of Ca2+ ions in the cytosol.
    • The signaling pathway is initiated by ZAP-70-mediated phosphorylation and activation of phospholipase Cγ (PLCγ).
    • PLCγ catalyzes the hydrolysis of PIP2, generating IP3, which binds to IP3 receptors on the ER membrane, stimulating the release of Ca2+ from the ER.

    Ras- and Rac-MAP Kinase Pathways

    • These pathways are initiated by ZAP-70-dependent phosphorylation and accumulation of adaptor proteins at the plasma membrane.
    • The pathways lead to the activation of distinct MAP kinases (ERK and JNK), which induce the expression of the transcription factor AP-1.

    PKCθ-NF-κB Pathway

    • PKCθ is activated by diacylglycerol, which is generated by PLC-mediated hydrolysis of membrane inositol lipids.
    • PKCθ acts through adaptor proteins recruited to the TCR complex to activate NF-κB.
    • NF-κB is released from its inhibitor IκB and moves to the nucleus, promoting the transcription of several genes.

    PI-3 Kinase Pathway

    • PI-3 kinase phosphorylates the membrane phospholipid PIP2 to generate PIP3.
    • PIP3 is required for the activation of Akt, which has many roles, including stimulating the expression of antiapoptotic proteins and promoting survival of antigen-stimulated T cells.

    T Cell Functional Responses

    • T cell activation leads to the secretion of cytokines, such as IL-2, which act on the T cells themselves and on other cells involved in immune defenses.
    • Cytokines are produced by effector T cells and serve diverse roles in host defense.
    • IL-2 is produced by activated CD4+ T cells and stimulates the survival and proliferation of T cells.
    • The IL-2 receptor is a three-chain molecule, and its expression is increased on activated T cells.

    Clonal Expansion

    • T lymphocytes activated by antigen and costimulation begin to proliferate, resulting in the expansion of antigen-specific clones.
    • The magnitude of clonal expansion is remarkable, especially for CD8+ T cells.
    • The expansion of CD4+ T cells is 100- to 1000-fold less than that of CD8+ cells.

    Differentiation of Naive T Cells into Effector Cells

    • Some of the progeny of antigen-stimulated, proliferating T cells differentiate into effector cells whose function is to eradicate infections.
    • Effector cells of the CD4+ lineage acquire the capacity to produce different sets of cytokines.
    • Effector cells of the CD8+ lineage acquire the ability to kill infected cells.

    Development of Memory T Lymphocytes

    • A fraction of antigen-activated T lymphocytes differentiates into long-lived memory cells.
    • Memory cells survive even after the infection is eradicated and antigen is no longer present.
    • Memory cells can be found in lymphoid organs, peripheral tissues, and the circulation.

    Migration of T Lymphocytes in Cell-Mediated Immune Reactions

    • T cells at different stages of their lives have to migrate in different ways.
    • Naive T cells migrate between blood and secondary lymphoid organs through HEVs (high endothelial venules).
    • HEVs are lined by specialized endothelial cells that express carbohydrate ligands that bind to L-selectin.### Migration of Naive T Cells
    • Naive T cells migrate through blood vessels in a multistep sequence similar to other leukocytes
    • Engagement of L-selectin with HEV (high endothelial venules) allows chemokines to bind to CCR7 on T cells
    • CCR7 transduces signals that activate LFA-1 (leukocyte function-associated antigen 1) on naive T cells, increasing binding affinity for ICAM-1 on HEV
    • Firm adhesion and arrest of rolling T cells occurs, followed by exit into the T cell zone of the lymph node

    Egress of T Cells from Lymph Nodes

    • Sphingosine 1-phosphate (S1P) plays a key role in T cell egress from lymph nodes
    • S1P levels are higher in blood and lymph than inside lymph nodes
    • S1P binds to its receptor, reducing expression on circulating naive T cells
    • When a naive T cell enters a node, S1P receptor expression increases, and the cell exits the node through efferent lymphatic vessels following the S1P gradient

    Activation and Differentiation of T Cells

    • Activated T cells do not express CCR7 or L-selectin, preventing re-entry into lymph nodes
    • Effector T cells migrate to sites of infection, expressing adhesion molecules and chemokine receptors that bind to ligands on vascular endothelium
    • Naive T cells do not express ligands for E- or P-selectin or receptors for chemokines produced at inflammatory sites, preventing migration into sites of infection

    Site-Specific Immune Response

    • Homing of effector T cells to a site of infection is independent of antigen recognition, but lymphocytes that recognize antigens are preferentially retained and activated at the site
    • Chemokines produced by macrophages and endothelial cells stimulate motility of transmigrating T cells
    • Effector T cells that leave the circulation and recognize microbial antigens presented by local tissue APCs become reactivated and contribute to killing microbes

    Decline of the Immune Response

    • After an infection is cleared, the immune response subsides, and the system returns to homeostasis
    • Survival and proliferation of T cells are maintained by antigen, costimulatory signals from CD28, and cytokines like IL-2
    • Once the infection is cleared, stimulated T cells die by apoptosis, and the response subsides within 1-2 weeks

    T Lymphocytes and Cell-Mediated Immunity

    • T lymphocytes perform multiple functions in defending against infections by various kinds of microbes.
    • They play a major role in cell-mediated immunity, which provides defense against infections by intracellular microbes.
    • Cell-mediated immunity is necessary to eliminate infections that occur inside cells, such as those caused by viruses and some bacteria.

    Phases of T Cell Responses

    • Naive T lymphocytes recognize antigens in peripheral lymphoid organs, which initiates proliferation and differentiation into effector and memory cells.
    • Effector cells perform their functions when they are activated by the same antigens in peripheral tissues or lymphoid organs.
    • The responses of naive T lymphocytes to cell-associated microbial antigens consist of a series of sequential steps, including:
      • Antigen recognition
      • Cytokine secretion and receptor expression
      • Clonal expansion
      • Differentiation into effector and memory cells

    Antigen Recognition and Costimulation

    • The initiation of T cell responses requires multiple receptors on the T cells recognizing ligands on antigen-presenting cells (APCs).
    • The T cell receptor (TCR) recognizes MHC-associated peptide antigens.
    • CD4 or CD8 coreceptors on the T cells recognize MHC molecules on the APC and help the TCR complex to deliver activating signals.
    • Adhesion molecules strengthen the binding of T cells to APCs.
    • Costimulators, such as B7-1 and B7-2, on APCs promote the responses of T cells to antigens.
    • Cytokines amplify the T cell response and direct it along various differentiation pathways.

    Role of Adhesion Molecules and Costimulation

    • Adhesion molecules, such as integrins, on T cells recognize ligands on APCs and stabilize the binding of T cells to APCs.
    • The binding of T cells to APCs must be stabilized for a sufficiently long period to achieve the necessary signaling threshold.
    • Costimulation ensures that naive T lymphocytes are activated fully by microbial antigens and not by harmless foreign substances or self-antigens.

    Inhibitory Receptors of T Cells

    • Inhibitory receptors, such as CTLA-4 and PD-1, are critical for limiting and terminating immune responses.
    • These receptors function to terminate responses of activated T cells and prevent immune responses against self-antigens.
    • Genetic deletion or blockade of these molecules can result in systemic autoimmune disease.

    Stimuli for Activation of CD8+ T Cells

    • The activation of CD8+ T cells is stimulated by recognition of class I MHC-associated peptides and requires costimulation and helper T cells.
    • The initiation of CD8+ T cell activation often requires cytosolic antigen from one cell (e.g., virus-infected or tumor cells) to be cross-presented by dendritic cells.
    • The differentiation of naive CD8+ T cells into fully active cytotoxic T lymphocytes (CTLs) and memory cells may require the concomitant activation of CD4+ helper T cells.### Helper T Cells and CD8+ T Cells
    • Human immunodeficiency virus (HIV) kills CD4+ but not CD8+ T cells, which is likely the explanation for the defective CTL responses to many viruses in HIV patients.
    • CD8+ T cells can respond to some viruses without the help of CD4+ T cells.

    Biochemical Pathways of T Cell Activation

    • T cell activation leads to protein synthesis, differentiation, and effector functions.
    • Antigen recognition triggers several biochemical mechanisms, including:
      • Kinase activation
      • Adaptor protein recruitment
      • Production of active transcription factors
    • The TCR complex, CD4/CD8 coreceptors, and CD28 coalesce at the center of the immune synapse, while integrins move to the periphery.
    • The immune synapse is required for optimal induction of activating signals in the T cell.

    Signaling Pathways

    • CD4 and CD8 coreceptors facilitate signaling through the protein tyrosine kinase Lck.
    • Lck phosphorylates ITAMs (immunoreceptor tyrosine-based activation motifs) in the CD3 and ζ chains.
    • The phosphorylated ITAMs in the ζ chain become docking sites for the tyrosine kinase ZAP-70.
    • ZAP-70 phosphorylates various adaptor proteins and enzymes, leading to additional signaling events.
    • The major signaling pathways linked to ζ-chain phosphorylation and ZAP-70 are:
      • Calcium-NFAT pathway
      • Ras- and Rac-MAP kinase pathways
      • PKCθ-NF-κB pathway
      • PI-3 kinase pathway

    Calcium-NFAT Pathway

    • NFAT (nuclear factor of activated T cells) is a transcription factor that is present in an inactive form in the cytoplasm of resting T cells.
    • NFAT activation and nuclear translocation depend on the concentration of Ca2+ ions in the cytosol.
    • The signaling pathway is initiated by ZAP-70-mediated phosphorylation and activation of phospholipase Cγ (PLCγ).
    • PLCγ catalyzes the hydrolysis of PIP2, generating IP3, which binds to IP3 receptors on the ER membrane, stimulating the release of Ca2+ from the ER.

    Ras- and Rac-MAP Kinase Pathways

    • These pathways are initiated by ZAP-70-dependent phosphorylation and accumulation of adaptor proteins at the plasma membrane.
    • The pathways lead to the activation of distinct MAP kinases (ERK and JNK), which induce the expression of the transcription factor AP-1.

    PKCθ-NF-κB Pathway

    • PKCθ is activated by diacylglycerol, which is generated by PLC-mediated hydrolysis of membrane inositol lipids.
    • PKCθ acts through adaptor proteins recruited to the TCR complex to activate NF-κB.
    • NF-κB is released from its inhibitor IκB and moves to the nucleus, promoting the transcription of several genes.

    PI-3 Kinase Pathway

    • PI-3 kinase phosphorylates the membrane phospholipid PIP2 to generate PIP3.
    • PIP3 is required for the activation of Akt, which has many roles, including stimulating the expression of antiapoptotic proteins and promoting survival of antigen-stimulated T cells.

    T Cell Functional Responses

    • T cell activation leads to the secretion of cytokines, such as IL-2, which act on the T cells themselves and on other cells involved in immune defenses.
    • Cytokines are produced by effector T cells and serve diverse roles in host defense.
    • IL-2 is produced by activated CD4+ T cells and stimulates the survival and proliferation of T cells.
    • The IL-2 receptor is a three-chain molecule, and its expression is increased on activated T cells.

    Clonal Expansion

    • T lymphocytes activated by antigen and costimulation begin to proliferate, resulting in the expansion of antigen-specific clones.
    • The magnitude of clonal expansion is remarkable, especially for CD8+ T cells.
    • The expansion of CD4+ T cells is 100- to 1000-fold less than that of CD8+ cells.

    Differentiation of Naive T Cells into Effector Cells

    • Some of the progeny of antigen-stimulated, proliferating T cells differentiate into effector cells whose function is to eradicate infections.
    • Effector cells of the CD4+ lineage acquire the capacity to produce different sets of cytokines.
    • Effector cells of the CD8+ lineage acquire the ability to kill infected cells.

    Development of Memory T Lymphocytes

    • A fraction of antigen-activated T lymphocytes differentiates into long-lived memory cells.
    • Memory cells survive even after the infection is eradicated and antigen is no longer present.
    • Memory cells can be found in lymphoid organs, peripheral tissues, and the circulation.

    Migration of T Lymphocytes in Cell-Mediated Immune Reactions

    • T cells at different stages of their lives have to migrate in different ways.
    • Naive T cells migrate between blood and secondary lymphoid organs through HEVs (high endothelial venules).
    • HEVs are lined by specialized endothelial cells that express carbohydrate ligands that bind to L-selectin.### Migration of Naive T Cells
    • Naive T cells migrate through blood vessels in a multistep sequence similar to other leukocytes
    • Engagement of L-selectin with HEV (high endothelial venules) allows chemokines to bind to CCR7 on T cells
    • CCR7 transduces signals that activate LFA-1 (leukocyte function-associated antigen 1) on naive T cells, increasing binding affinity for ICAM-1 on HEV
    • Firm adhesion and arrest of rolling T cells occurs, followed by exit into the T cell zone of the lymph node

    Egress of T Cells from Lymph Nodes

    • Sphingosine 1-phosphate (S1P) plays a key role in T cell egress from lymph nodes
    • S1P levels are higher in blood and lymph than inside lymph nodes
    • S1P binds to its receptor, reducing expression on circulating naive T cells
    • When a naive T cell enters a node, S1P receptor expression increases, and the cell exits the node through efferent lymphatic vessels following the S1P gradient

    Activation and Differentiation of T Cells

    • Activated T cells do not express CCR7 or L-selectin, preventing re-entry into lymph nodes
    • Effector T cells migrate to sites of infection, expressing adhesion molecules and chemokine receptors that bind to ligands on vascular endothelium
    • Naive T cells do not express ligands for E- or P-selectin or receptors for chemokines produced at inflammatory sites, preventing migration into sites of infection

    Site-Specific Immune Response

    • Homing of effector T cells to a site of infection is independent of antigen recognition, but lymphocytes that recognize antigens are preferentially retained and activated at the site
    • Chemokines produced by macrophages and endothelial cells stimulate motility of transmigrating T cells
    • Effector T cells that leave the circulation and recognize microbial antigens presented by local tissue APCs become reactivated and contribute to killing microbes

    Decline of the Immune Response

    • After an infection is cleared, the immune response subsides, and the system returns to homeostasis
    • Survival and proliferation of T cells are maintained by antigen, costimulatory signals from CD28, and cytokines like IL-2
    • Once the infection is cleared, stimulated T cells die by apoptosis, and the response subsides within 1-2 weeks

    T Lymphocytes and Cell-Mediated Immunity

    • T lymphocytes perform multiple functions in defending against infections by various kinds of microbes.
    • They play a major role in cell-mediated immunity, which provides defense against infections by intracellular microbes.
    • Cell-mediated immunity is necessary to eliminate infections that occur inside cells, such as those caused by viruses and some bacteria.

    Phases of T Cell Responses

    • Naive T lymphocytes recognize antigens in peripheral lymphoid organs, which initiates proliferation and differentiation into effector and memory cells.
    • Effector cells perform their functions when they are activated by the same antigens in peripheral tissues or lymphoid organs.
    • The responses of naive T lymphocytes to cell-associated microbial antigens consist of a series of sequential steps, including:
      • Antigen recognition
      • Cytokine secretion and receptor expression
      • Clonal expansion
      • Differentiation into effector and memory cells

    Antigen Recognition and Costimulation

    • The initiation of T cell responses requires multiple receptors on the T cells recognizing ligands on antigen-presenting cells (APCs).
    • The T cell receptor (TCR) recognizes MHC-associated peptide antigens.
    • CD4 or CD8 coreceptors on the T cells recognize MHC molecules on the APC and help the TCR complex to deliver activating signals.
    • Adhesion molecules strengthen the binding of T cells to APCs.
    • Costimulators, such as B7-1 and B7-2, on APCs promote the responses of T cells to antigens.
    • Cytokines amplify the T cell response and direct it along various differentiation pathways.

    Role of Adhesion Molecules and Costimulation

    • Adhesion molecules, such as integrins, on T cells recognize ligands on APCs and stabilize the binding of T cells to APCs.
    • The binding of T cells to APCs must be stabilized for a sufficiently long period to achieve the necessary signaling threshold.
    • Costimulation ensures that naive T lymphocytes are activated fully by microbial antigens and not by harmless foreign substances or self-antigens.

    Inhibitory Receptors of T Cells

    • Inhibitory receptors, such as CTLA-4 and PD-1, are critical for limiting and terminating immune responses.
    • These receptors function to terminate responses of activated T cells and prevent immune responses against self-antigens.
    • Genetic deletion or blockade of these molecules can result in systemic autoimmune disease.

    Stimuli for Activation of CD8+ T Cells

    • The activation of CD8+ T cells is stimulated by recognition of class I MHC-associated peptides and requires costimulation and helper T cells.
    • The initiation of CD8+ T cell activation often requires cytosolic antigen from one cell (e.g., virus-infected or tumor cells) to be cross-presented by dendritic cells.
    • The differentiation of naive CD8+ T cells into fully active cytotoxic T lymphocytes (CTLs) and memory cells may require the concomitant activation of CD4+ helper T cells.### Helper T Cells and CD8+ T Cells
    • Human immunodeficiency virus (HIV) kills CD4+ but not CD8+ T cells, which is likely the explanation for the defective CTL responses to many viruses in HIV patients.
    • CD8+ T cells can respond to some viruses without the help of CD4+ T cells.

    Biochemical Pathways of T Cell Activation

    • T cell activation leads to protein synthesis, differentiation, and effector functions.
    • Antigen recognition triggers several biochemical mechanisms, including:
      • Kinase activation
      • Adaptor protein recruitment
      • Production of active transcription factors
    • The TCR complex, CD4/CD8 coreceptors, and CD28 coalesce at the center of the immune synapse, while integrins move to the periphery.
    • The immune synapse is required for optimal induction of activating signals in the T cell.

    Signaling Pathways

    • CD4 and CD8 coreceptors facilitate signaling through the protein tyrosine kinase Lck.
    • Lck phosphorylates ITAMs (immunoreceptor tyrosine-based activation motifs) in the CD3 and ζ chains.
    • The phosphorylated ITAMs in the ζ chain become docking sites for the tyrosine kinase ZAP-70.
    • ZAP-70 phosphorylates various adaptor proteins and enzymes, leading to additional signaling events.
    • The major signaling pathways linked to ζ-chain phosphorylation and ZAP-70 are:
      • Calcium-NFAT pathway
      • Ras- and Rac-MAP kinase pathways
      • PKCθ-NF-κB pathway
      • PI-3 kinase pathway

    Calcium-NFAT Pathway

    • NFAT (nuclear factor of activated T cells) is a transcription factor that is present in an inactive form in the cytoplasm of resting T cells.
    • NFAT activation and nuclear translocation depend on the concentration of Ca2+ ions in the cytosol.
    • The signaling pathway is initiated by ZAP-70-mediated phosphorylation and activation of phospholipase Cγ (PLCγ).
    • PLCγ catalyzes the hydrolysis of PIP2, generating IP3, which binds to IP3 receptors on the ER membrane, stimulating the release of Ca2+ from the ER.

    Ras- and Rac-MAP Kinase Pathways

    • These pathways are initiated by ZAP-70-dependent phosphorylation and accumulation of adaptor proteins at the plasma membrane.
    • The pathways lead to the activation of distinct MAP kinases (ERK and JNK), which induce the expression of the transcription factor AP-1.

    PKCθ-NF-κB Pathway

    • PKCθ is activated by diacylglycerol, which is generated by PLC-mediated hydrolysis of membrane inositol lipids.
    • PKCθ acts through adaptor proteins recruited to the TCR complex to activate NF-κB.
    • NF-κB is released from its inhibitor IκB and moves to the nucleus, promoting the transcription of several genes.

    PI-3 Kinase Pathway

    • PI-3 kinase phosphorylates the membrane phospholipid PIP2 to generate PIP3.
    • PIP3 is required for the activation of Akt, which has many roles, including stimulating the expression of antiapoptotic proteins and promoting survival of antigen-stimulated T cells.

    T Cell Functional Responses

    • T cell activation leads to the secretion of cytokines, such as IL-2, which act on the T cells themselves and on other cells involved in immune defenses.
    • Cytokines are produced by effector T cells and serve diverse roles in host defense.
    • IL-2 is produced by activated CD4+ T cells and stimulates the survival and proliferation of T cells.
    • The IL-2 receptor is a three-chain molecule, and its expression is increased on activated T cells.

    Clonal Expansion

    • T lymphocytes activated by antigen and costimulation begin to proliferate, resulting in the expansion of antigen-specific clones.
    • The magnitude of clonal expansion is remarkable, especially for CD8+ T cells.
    • The expansion of CD4+ T cells is 100- to 1000-fold less than that of CD8+ cells.

    Differentiation of Naive T Cells into Effector Cells

    • Some of the progeny of antigen-stimulated, proliferating T cells differentiate into effector cells whose function is to eradicate infections.
    • Effector cells of the CD4+ lineage acquire the capacity to produce different sets of cytokines.
    • Effector cells of the CD8+ lineage acquire the ability to kill infected cells.

    Development of Memory T Lymphocytes

    • A fraction of antigen-activated T lymphocytes differentiates into long-lived memory cells.
    • Memory cells survive even after the infection is eradicated and antigen is no longer present.
    • Memory cells can be found in lymphoid organs, peripheral tissues, and the circulation.

    Migration of T Lymphocytes in Cell-Mediated Immune Reactions

    • T cells at different stages of their lives have to migrate in different ways.
    • Naive T cells migrate between blood and secondary lymphoid organs through HEVs (high endothelial venules).
    • HEVs are lined by specialized endothelial cells that express carbohydrate ligands that bind to L-selectin.### Migration of Naive T Cells
    • Naive T cells migrate through blood vessels in a multistep sequence similar to other leukocytes
    • Engagement of L-selectin with HEV (high endothelial venules) allows chemokines to bind to CCR7 on T cells
    • CCR7 transduces signals that activate LFA-1 (leukocyte function-associated antigen 1) on naive T cells, increasing binding affinity for ICAM-1 on HEV
    • Firm adhesion and arrest of rolling T cells occurs, followed by exit into the T cell zone of the lymph node

    Egress of T Cells from Lymph Nodes

    • Sphingosine 1-phosphate (S1P) plays a key role in T cell egress from lymph nodes
    • S1P levels are higher in blood and lymph than inside lymph nodes
    • S1P binds to its receptor, reducing expression on circulating naive T cells
    • When a naive T cell enters a node, S1P receptor expression increases, and the cell exits the node through efferent lymphatic vessels following the S1P gradient

    Activation and Differentiation of T Cells

    • Activated T cells do not express CCR7 or L-selectin, preventing re-entry into lymph nodes
    • Effector T cells migrate to sites of infection, expressing adhesion molecules and chemokine receptors that bind to ligands on vascular endothelium
    • Naive T cells do not express ligands for E- or P-selectin or receptors for chemokines produced at inflammatory sites, preventing migration into sites of infection

    Site-Specific Immune Response

    • Homing of effector T cells to a site of infection is independent of antigen recognition, but lymphocytes that recognize antigens are preferentially retained and activated at the site
    • Chemokines produced by macrophages and endothelial cells stimulate motility of transmigrating T cells
    • Effector T cells that leave the circulation and recognize microbial antigens presented by local tissue APCs become reactivated and contribute to killing microbes

    Decline of the Immune Response

    • After an infection is cleared, the immune response subsides, and the system returns to homeostasis
    • Survival and proliferation of T cells are maintained by antigen, costimulatory signals from CD28, and cytokines like IL-2
    • Once the infection is cleared, stimulated T cells die by apoptosis, and the response subsides within 1-2 weeks

    T Lymphocytes and Cell-Mediated Immunity

    • T lymphocytes perform multiple functions in defending against infections by various kinds of microbes.
    • They play a major role in cell-mediated immunity, which provides defense against infections by intracellular microbes.
    • Cell-mediated immunity is necessary to eliminate infections that occur inside cells, such as those caused by viruses and some bacteria.

    Phases of T Cell Responses

    • Naive T lymphocytes recognize antigens in peripheral lymphoid organs, which initiates proliferation and differentiation into effector and memory cells.
    • Effector cells perform their functions when they are activated by the same antigens in peripheral tissues or lymphoid organs.
    • The responses of naive T lymphocytes to cell-associated microbial antigens consist of a series of sequential steps, including:
      • Antigen recognition
      • Cytokine secretion and receptor expression
      • Clonal expansion
      • Differentiation into effector and memory cells

    Antigen Recognition and Costimulation

    • The initiation of T cell responses requires multiple receptors on the T cells recognizing ligands on antigen-presenting cells (APCs).
    • The T cell receptor (TCR) recognizes MHC-associated peptide antigens.
    • CD4 or CD8 coreceptors on the T cells recognize MHC molecules on the APC and help the TCR complex to deliver activating signals.
    • Adhesion molecules strengthen the binding of T cells to APCs.
    • Costimulators, such as B7-1 and B7-2, on APCs promote the responses of T cells to antigens.
    • Cytokines amplify the T cell response and direct it along various differentiation pathways.

    Role of Adhesion Molecules and Costimulation

    • Adhesion molecules, such as integrins, on T cells recognize ligands on APCs and stabilize the binding of T cells to APCs.
    • The binding of T cells to APCs must be stabilized for a sufficiently long period to achieve the necessary signaling threshold.
    • Costimulation ensures that naive T lymphocytes are activated fully by microbial antigens and not by harmless foreign substances or self-antigens.

    Inhibitory Receptors of T Cells

    • Inhibitory receptors, such as CTLA-4 and PD-1, are critical for limiting and terminating immune responses.
    • These receptors function to terminate responses of activated T cells and prevent immune responses against self-antigens.
    • Genetic deletion or blockade of these molecules can result in systemic autoimmune disease.

    Stimuli for Activation of CD8+ T Cells

    • The activation of CD8+ T cells is stimulated by recognition of class I MHC-associated peptides and requires costimulation and helper T cells.
    • The initiation of CD8+ T cell activation often requires cytosolic antigen from one cell (e.g., virus-infected or tumor cells) to be cross-presented by dendritic cells.
    • The differentiation of naive CD8+ T cells into fully active cytotoxic T lymphocytes (CTLs) and memory cells may require the concomitant activation of CD4+ helper T cells.### Helper T Cells and CD8+ T Cells
    • Human immunodeficiency virus (HIV) kills CD4+ but not CD8+ T cells, which is likely the explanation for the defective CTL responses to many viruses in HIV patients.
    • CD8+ T cells can respond to some viruses without the help of CD4+ T cells.

    Biochemical Pathways of T Cell Activation

    • T cell activation leads to protein synthesis, differentiation, and effector functions.
    • Antigen recognition triggers several biochemical mechanisms, including:
      • Kinase activation
      • Adaptor protein recruitment
      • Production of active transcription factors
    • The TCR complex, CD4/CD8 coreceptors, and CD28 coalesce at the center of the immune synapse, while integrins move to the periphery.
    • The immune synapse is required for optimal induction of activating signals in the T cell.

    Signaling Pathways

    • CD4 and CD8 coreceptors facilitate signaling through the protein tyrosine kinase Lck.
    • Lck phosphorylates ITAMs (immunoreceptor tyrosine-based activation motifs) in the CD3 and ζ chains.
    • The phosphorylated ITAMs in the ζ chain become docking sites for the tyrosine kinase ZAP-70.
    • ZAP-70 phosphorylates various adaptor proteins and enzymes, leading to additional signaling events.
    • The major signaling pathways linked to ζ-chain phosphorylation and ZAP-70 are:
      • Calcium-NFAT pathway
      • Ras- and Rac-MAP kinase pathways
      • PKCθ-NF-κB pathway
      • PI-3 kinase pathway

    Calcium-NFAT Pathway

    • NFAT (nuclear factor of activated T cells) is a transcription factor that is present in an inactive form in the cytoplasm of resting T cells.
    • NFAT activation and nuclear translocation depend on the concentration of Ca2+ ions in the cytosol.
    • The signaling pathway is initiated by ZAP-70-mediated phosphorylation and activation of phospholipase Cγ (PLCγ).
    • PLCγ catalyzes the hydrolysis of PIP2, generating IP3, which binds to IP3 receptors on the ER membrane, stimulating the release of Ca2+ from the ER.

    Ras- and Rac-MAP Kinase Pathways

    • These pathways are initiated by ZAP-70-dependent phosphorylation and accumulation of adaptor proteins at the plasma membrane.
    • The pathways lead to the activation of distinct MAP kinases (ERK and JNK), which induce the expression of the transcription factor AP-1.

    PKCθ-NF-κB Pathway

    • PKCθ is activated by diacylglycerol, which is generated by PLC-mediated hydrolysis of membrane inositol lipids.
    • PKCθ acts through adaptor proteins recruited to the TCR complex to activate NF-κB.
    • NF-κB is released from its inhibitor IκB and moves to the nucleus, promoting the transcription of several genes.

    PI-3 Kinase Pathway

    • PI-3 kinase phosphorylates the membrane phospholipid PIP2 to generate PIP3.
    • PIP3 is required for the activation of Akt, which has many roles, including stimulating the expression of antiapoptotic proteins and promoting survival of antigen-stimulated T cells.

    T Cell Functional Responses

    • T cell activation leads to the secretion of cytokines, such as IL-2, which act on the T cells themselves and on other cells involved in immune defenses.
    • Cytokines are produced by effector T cells and serve diverse roles in host defense.
    • IL-2 is produced by activated CD4+ T cells and stimulates the survival and proliferation of T cells.
    • The IL-2 receptor is a three-chain molecule, and its expression is increased on activated T cells.

    Clonal Expansion

    • T lymphocytes activated by antigen and costimulation begin to proliferate, resulting in the expansion of antigen-specific clones.
    • The magnitude of clonal expansion is remarkable, especially for CD8+ T cells.
    • The expansion of CD4+ T cells is 100- to 1000-fold less than that of CD8+ cells.

    Differentiation of Naive T Cells into Effector Cells

    • Some of the progeny of antigen-stimulated, proliferating T cells differentiate into effector cells whose function is to eradicate infections.
    • Effector cells of the CD4+ lineage acquire the capacity to produce different sets of cytokines.
    • Effector cells of the CD8+ lineage acquire the ability to kill infected cells.

    Development of Memory T Lymphocytes

    • A fraction of antigen-activated T lymphocytes differentiates into long-lived memory cells.
    • Memory cells survive even after the infection is eradicated and antigen is no longer present.
    • Memory cells can be found in lymphoid organs, peripheral tissues, and the circulation.

    Migration of T Lymphocytes in Cell-Mediated Immune Reactions

    • T cells at different stages of their lives have to migrate in different ways.
    • Naive T cells migrate between blood and secondary lymphoid organs through HEVs (high endothelial venules).
    • HEVs are lined by specialized endothelial cells that express carbohydrate ligands that bind to L-selectin.### Migration of Naive T Cells
    • Naive T cells migrate through blood vessels in a multistep sequence similar to other leukocytes
    • Engagement of L-selectin with HEV (high endothelial venules) allows chemokines to bind to CCR7 on T cells
    • CCR7 transduces signals that activate LFA-1 (leukocyte function-associated antigen 1) on naive T cells, increasing binding affinity for ICAM-1 on HEV
    • Firm adhesion and arrest of rolling T cells occurs, followed by exit into the T cell zone of the lymph node

    Egress of T Cells from Lymph Nodes

    • Sphingosine 1-phosphate (S1P) plays a key role in T cell egress from lymph nodes
    • S1P levels are higher in blood and lymph than inside lymph nodes
    • S1P binds to its receptor, reducing expression on circulating naive T cells
    • When a naive T cell enters a node, S1P receptor expression increases, and the cell exits the node through efferent lymphatic vessels following the S1P gradient

    Activation and Differentiation of T Cells

    • Activated T cells do not express CCR7 or L-selectin, preventing re-entry into lymph nodes
    • Effector T cells migrate to sites of infection, expressing adhesion molecules and chemokine receptors that bind to ligands on vascular endothelium
    • Naive T cells do not express ligands for E- or P-selectin or receptors for chemokines produced at inflammatory sites, preventing migration into sites of infection

    Site-Specific Immune Response

    • Homing of effector T cells to a site of infection is independent of antigen recognition, but lymphocytes that recognize antigens are preferentially retained and activated at the site
    • Chemokines produced by macrophages and endothelial cells stimulate motility of transmigrating T cells
    • Effector T cells that leave the circulation and recognize microbial antigens presented by local tissue APCs become reactivated and contribute to killing microbes

    Decline of the Immune Response

    • After an infection is cleared, the immune response subsides, and the system returns to homeostasis
    • Survival and proliferation of T cells are maintained by antigen, costimulatory signals from CD28, and cytokines like IL-2
    • Once the infection is cleared, stimulated T cells die by apoptosis, and the response subsides within 1-2 weeks

    T Lymphocytes and Cell-Mediated Immunity

    • T lymphocytes perform multiple functions in defending against infections by various kinds of microbes.
    • They play a major role in cell-mediated immunity, which provides defense against infections by intracellular microbes.
    • Cell-mediated immunity is necessary to eliminate infections that occur inside cells, such as those caused by viruses and some bacteria.

    Phases of T Cell Responses

    • Naive T lymphocytes recognize antigens in peripheral lymphoid organs, which initiates proliferation and differentiation into effector and memory cells.
    • Effector cells perform their functions when they are activated by the same antigens in peripheral tissues or lymphoid organs.
    • The responses of naive T lymphocytes to cell-associated microbial antigens consist of a series of sequential steps, including:
      • Antigen recognition
      • Cytokine secretion and receptor expression
      • Clonal expansion
      • Differentiation into effector and memory cells

    Antigen Recognition and Costimulation

    • The initiation of T cell responses requires multiple receptors on the T cells recognizing ligands on antigen-presenting cells (APCs).
    • The T cell receptor (TCR) recognizes MHC-associated peptide antigens.
    • CD4 or CD8 coreceptors on the T cells recognize MHC molecules on the APC and help the TCR complex to deliver activating signals.
    • Adhesion molecules strengthen the binding of T cells to APCs.
    • Costimulators, such as B7-1 and B7-2, on APCs promote the responses of T cells to antigens.
    • Cytokines amplify the T cell response and direct it along various differentiation pathways.

    Role of Adhesion Molecules and Costimulation

    • Adhesion molecules, such as integrins, on T cells recognize ligands on APCs and stabilize the binding of T cells to APCs.
    • The binding of T cells to APCs must be stabilized for a sufficiently long period to achieve the necessary signaling threshold.
    • Costimulation ensures that naive T lymphocytes are activated fully by microbial antigens and not by harmless foreign substances or self-antigens.

    Inhibitory Receptors of T Cells

    • Inhibitory receptors, such as CTLA-4 and PD-1, are critical for limiting and terminating immune responses.
    • These receptors function to terminate responses of activated T cells and prevent immune responses against self-antigens.
    • Genetic deletion or blockade of these molecules can result in systemic autoimmune disease.

    Stimuli for Activation of CD8+ T Cells

    • The activation of CD8+ T cells is stimulated by recognition of class I MHC-associated peptides and requires costimulation and helper T cells.
    • The initiation of CD8+ T cell activation often requires cytosolic antigen from one cell (e.g., virus-infected or tumor cells) to be cross-presented by dendritic cells.
    • The differentiation of naive CD8+ T cells into fully active cytotoxic T lymphocytes (CTLs) and memory cells may require the concomitant activation of CD4+ helper T cells.### Helper T Cells and CD8+ T Cells
    • Human immunodeficiency virus (HIV) kills CD4+ but not CD8+ T cells, which is likely the explanation for the defective CTL responses to many viruses in HIV patients.
    • CD8+ T cells can respond to some viruses without the help of CD4+ T cells.

    Biochemical Pathways of T Cell Activation

    • T cell activation leads to protein synthesis, differentiation, and effector functions.
    • Antigen recognition triggers several biochemical mechanisms, including:
      • Kinase activation
      • Adaptor protein recruitment
      • Production of active transcription factors
    • The TCR complex, CD4/CD8 coreceptors, and CD28 coalesce at the center of the immune synapse, while integrins move to the periphery.
    • The immune synapse is required for optimal induction of activating signals in the T cell.

    Signaling Pathways

    • CD4 and CD8 coreceptors facilitate signaling through the protein tyrosine kinase Lck.
    • Lck phosphorylates ITAMs (immunoreceptor tyrosine-based activation motifs) in the CD3 and ζ chains.
    • The phosphorylated ITAMs in the ζ chain become docking sites for the tyrosine kinase ZAP-70.
    • ZAP-70 phosphorylates various adaptor proteins and enzymes, leading to additional signaling events.
    • The major signaling pathways linked to ζ-chain phosphorylation and ZAP-70 are:
      • Calcium-NFAT pathway
      • Ras- and Rac-MAP kinase pathways
      • PKCθ-NF-κB pathway
      • PI-3 kinase pathway

    Calcium-NFAT Pathway

    • NFAT (nuclear factor of activated T cells) is a transcription factor that is present in an inactive form in the cytoplasm of resting T cells.
    • NFAT activation and nuclear translocation depend on the concentration of Ca2+ ions in the cytosol.
    • The signaling pathway is initiated by ZAP-70-mediated phosphorylation and activation of phospholipase Cγ (PLCγ).
    • PLCγ catalyzes the hydrolysis of PIP2, generating IP3, which binds to IP3 receptors on the ER membrane, stimulating the release of Ca2+ from the ER.

    Ras- and Rac-MAP Kinase Pathways

    • These pathways are initiated by ZAP-70-dependent phosphorylation and accumulation of adaptor proteins at the plasma membrane.
    • The pathways lead to the activation of distinct MAP kinases (ERK and JNK), which induce the expression of the transcription factor AP-1.

    PKCθ-NF-κB Pathway

    • PKCθ is activated by diacylglycerol, which is generated by PLC-mediated hydrolysis of membrane inositol lipids.
    • PKCθ acts through adaptor proteins recruited to the TCR complex to activate NF-κB.
    • NF-κB is released from its inhibitor IκB and moves to the nucleus, promoting the transcription of several genes.

    PI-3 Kinase Pathway

    • PI-3 kinase phosphorylates the membrane phospholipid PIP2 to generate PIP3.
    • PIP3 is required for the activation of Akt, which has many roles, including stimulating the expression of antiapoptotic proteins and promoting survival of antigen-stimulated T cells.

    T Cell Functional Responses

    • T cell activation leads to the secretion of cytokines, such as IL-2, which act on the T cells themselves and on other cells involved in immune defenses.
    • Cytokines are produced by effector T cells and serve diverse roles in host defense.
    • IL-2 is produced by activated CD4+ T cells and stimulates the survival and proliferation of T cells.
    • The IL-2 receptor is a three-chain molecule, and its expression is increased on activated T cells.

    Clonal Expansion

    • T lymphocytes activated by antigen and costimulation begin to proliferate, resulting in the expansion of antigen-specific clones.
    • The magnitude of clonal expansion is remarkable, especially for CD8+ T cells.
    • The expansion of CD4+ T cells is 100- to 1000-fold less than that of CD8+ cells.

    Differentiation of Naive T Cells into Effector Cells

    • Some of the progeny of antigen-stimulated, proliferating T cells differentiate into effector cells whose function is to eradicate infections.
    • Effector cells of the CD4+ lineage acquire the capacity to produce different sets of cytokines.
    • Effector cells of the CD8+ lineage acquire the ability to kill infected cells.

    Development of Memory T Lymphocytes

    • A fraction of antigen-activated T lymphocytes differentiates into long-lived memory cells.
    • Memory cells survive even after the infection is eradicated and antigen is no longer present.
    • Memory cells can be found in lymphoid organs, peripheral tissues, and the circulation.

    Migration of T Lymphocytes in Cell-Mediated Immune Reactions

    • T cells at different stages of their lives have to migrate in different ways.
    • Naive T cells migrate between blood and secondary lymphoid organs through HEVs (high endothelial venules).
    • HEVs are lined by specialized endothelial cells that express carbohydrate ligands that bind to L-selectin.### Migration of Naive T Cells
    • Naive T cells migrate through blood vessels in a multistep sequence similar to other leukocytes
    • Engagement of L-selectin with HEV (high endothelial venules) allows chemokines to bind to CCR7 on T cells
    • CCR7 transduces signals that activate LFA-1 (leukocyte function-associated antigen 1) on naive T cells, increasing binding affinity for ICAM-1 on HEV
    • Firm adhesion and arrest of rolling T cells occurs, followed by exit into the T cell zone of the lymph node

    Egress of T Cells from Lymph Nodes

    • Sphingosine 1-phosphate (S1P) plays a key role in T cell egress from lymph nodes
    • S1P levels are higher in blood and lymph than inside lymph nodes
    • S1P binds to its receptor, reducing expression on circulating naive T cells
    • When a naive T cell enters a node, S1P receptor expression increases, and the cell exits the node through efferent lymphatic vessels following the S1P gradient

    Activation and Differentiation of T Cells

    • Activated T cells do not express CCR7 or L-selectin, preventing re-entry into lymph nodes
    • Effector T cells migrate to sites of infection, expressing adhesion molecules and chemokine receptors that bind to ligands on vascular endothelium
    • Naive T cells do not express ligands for E- or P-selectin or receptors for chemokines produced at inflammatory sites, preventing migration into sites of infection

    Site-Specific Immune Response

    • Homing of effector T cells to a site of infection is independent of antigen recognition, but lymphocytes that recognize antigens are preferentially retained and activated at the site
    • Chemokines produced by macrophages and endothelial cells stimulate motility of transmigrating T cells
    • Effector T cells that leave the circulation and recognize microbial antigens presented by local tissue APCs become reactivated and contribute to killing microbes

    Decline of the Immune Response

    • After an infection is cleared, the immune response subsides, and the system returns to homeostasis
    • Survival and proliferation of T cells are maintained by antigen, costimulatory signals from CD28, and cytokines like IL-2
    • Once the infection is cleared, stimulated T cells die by apoptosis, and the response subsides within 1-2 weeks

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    Learn about the role of T lymphocytes in defending against infections by intracellular microbes and how they eliminate microbes through cell-mediated immune responses.

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