Immunology Chapter on B and T Cells
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Immunology Chapter on B and T Cells

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Questions and Answers

What is the primary function of B cells?

  • Produce antibodies to fight pathogens (correct)
  • Mature into cytotoxic T cells
  • Increase inflammation in tissues
  • Attack virus-infected cells directly

    • Naïve T cells have the ability to bind to MHC class I molecules.

    False

    What process contributes to the diversity of B Cell Receptors (BCRs)?

    Gene segment rearrangement (VDJ recombination)

    T cell receptors (TCRs) are assembled through genetic __________ and junctional diversity.

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

    Match the following T cell types with their primary functions:

    <p>CD8 T cells = Killer T Cells CD4 T cells = Helper T Cells Naïve T cells = Circulate in blood and lymph γ/δ T cells = Non-traditional T cells with unclear biology</p> Signup and view all the answers

    What triggers the negative selection process in T cells?

    <p>Recognition of self-peptides by mTEC</p> Signup and view all the answers

    All T cells undergo positive selection before entering the circulation.

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

    What is an epitope?

    <p>The specific piece of an antigen that is bound by an antibody</p> Signup and view all the answers

    What is the primary function of helper T cells (CD4)?

    <p>Produce cytokines to direct the immune response</p> Signup and view all the answers

    Immunoglobulins can only bind to proteins.

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

    The protein that enables medullary thymic epithelial cells to express tissue-specific proteins is called _____ .

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

    What does BCR stand for?

    <p>B Cell Receptor</p> Signup and view all the answers

    The heavy chain segments in BCR development are located on chromosome ______.

    <p>14</p> Signup and view all the answers

    Match the following T cell activation steps with their descriptions:

    <p>Step 1 = Binding of antigen + MHC by TCR + CD coreceptor Step 2 = Co-stimulation via CD28 and B7 Step 3 = Release of IL-2 for clonal expansion</p> Signup and view all the answers

    Match the following terms with their definitions:

    <p>VDJ recombination = A process that generates diversity in BCRs Junctional diversity = Variation caused by base pairs being added or removed B Cell Receptor (BCR) = The receptor on B cells that binds to antigens Epitope = The part of the antigen recognized by antibodies</p> Signup and view all the answers

    Which of the following processes generates diversity in B Cell Receptors?

    <p>VDJ recombination and junctional diversity</p> Signup and view all the answers

    B cells start with different DNA prior to BCR development.

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

    Explain how self-reactive receptors are prevented during BCR development.

    <p>Through a selection process where B cells that bind strongly to self-antigens are eliminated or undergo receptor editing.</p> Signup and view all the answers

    Which type of MHC molecule is expressed by all cells?

    <p>MHC I</p> Signup and view all the answers

    Class II MHC molecules present intracellular peptides.

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

    What type of T cell interacts with MHC Class II molecules?

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

    The binding groove of Class I MHC is __________, while the binding groove of Class II MHC is __________.

    <p>closed, open</p> Signup and view all the answers

    Match the following features with the corresponding MHC class:

    <p>Expressed by all cells = MHC I Binds larger peptides (13-25 amino acids) = MHC II Presents antigens to CD8 T cells = MHC I Expressed only by antigen presenting cells = MHC II</p> Signup and view all the answers

    What type of antigens do CD8 T cells inspect when interacting with MHC Class I?

    <p>Endogenous antigens</p> Signup and view all the answers

    What are the two main types of antigen presenting cells?

    <p>Dendritic cells and macrophages</p> Signup and view all the answers

    MHC Class II molecules can present antigens derived from intracellular pathogens.

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

    What is the main role of IL-12 produced by dendritic cells?

    <p>Activate macrophages and NK cells</p> Signup and view all the answers

    T cell activation requires antigen presentation by dendritic cells without any additional signals.

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

    Name one type of helper T cell involved in responding to extracellular pathogens.

    <p>Tfh (T follicular helper cells)</p> Signup and view all the answers

    DCs from sites with _______ lead to the production of Th2 helper T cells.

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

    Match each T helper cell type with its primary function:

    <p>Th1 = Activates macrophages and NK cells Th2 = Stimulates B cells to produce IgE Th17 = Recruits neutrophils to sites of infection Tfh = Activates B cells in germinal centers</p> Signup and view all the answers

    Which cytokines are released by Th17 cells?

    <p>TGFβ and IL-6</p> Signup and view all the answers

    B cells can directly recognize and bind to presented antigens on MHC molecules.

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

    What effect do CD8 T cells have on infected cells?

    <p>Induce apoptosis</p> Signup and view all the answers

    Tregs are induced by _______ and secrete IL-10.

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

    Match the following immune components with their roles:

    <p>Perforin = Forms pores in target cell membranes Granzyme B = Induces apoptosis pathway IFNγ = Upregulates MHC class I expression IL-10 = Reduces T cell proliferation</p> Signup and view all the answers

    What role do checkpoint proteins like PD-1 play in T cell function?

    <p>Inhibit T cell function</p> Signup and view all the answers

    B cell memory consists of long-lived plasma cells that produce antibodies continually.

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

    What are the memory T cell types that reside in secondary lymphoid organs called?

    <p>Central memory T cells</p> Signup and view all the answers

    Cells that strongly bind to self-molecules during development undergo _______.

    <p>deletion or tolerance</p> Signup and view all the answers

    What is the primary role of CTLs in the immune response?

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

    Study Notes

    Immunoglobulins

    • Immunoglobulins are composed of four polypeptide chains: two identical heavy chains and two identical light chains.
    • They bind to “native” macromolecular antigens.
    • Antigens are any molecules that can be bound by an antibody, B cell receptor, or T cell receptor.
    • Epitopes are the specific pieces of the antigen that are directly bound.
    • Immunoglobulins can bind any type of macromolecule: protein, carbohydrate, lipid, etc.

    B Cell Receptor (BCR)

    • Structurally identical to antibody + retention sequence on Fc domain.
    • Composed of two proteins: heavy chain + light chain.
    • Diversity of BCRs arise through: genetic recombination (VDJ recombination), junctional diversity.

    BCR Development

    • All B cells start with the same DNA.
    • Diversity is generated through V(D)J recombination.
    • Heavy chain: Chromosome 14 has 4 types of gene segments: V, D, J, C.
    • Heavy chain: ~40 V segments, 25 Ds, 6 Js, 10 Cs.
    • Heavy chain: B cell chooses (at random) one of each segment (VDJ).
    • Light chain: Same process but only with VJ.
    • Heavy + light chain combinations = 10 million options.
    • Junctional diversity (base pairs added/removed) = 100 million options.

    Creation of BCR

    • V(D)J gene rearrangement: ex.Ig heavy chain: One V segment, one D segment, one J segment randomly chosen.
    • DNA recombination occurs and removes the DNA between these segments.
    • The resulting VDJ recombined segment can be transcribed.
    • V(D)J gene rearrangement: ex.Ig light chain: One V segment, one J segment randomly chosen.
    • DNA recombination occurs and removes the DNA between these segments.
    • The resulting VJ recombined segment can be transcribed.

    Generation of Diversity: Immunoglobulins and TCRs

    • Problems with random generation of Igs and TCRs: How are self-reactive receptors prevented? How is the “right” receptor made at the “right” time?

    B Cell Review

    • B cells produce antibodies to fight pathogens.
    • Antibody class determine effector functions (IgM, IgG, IgA, IgE).
    • General antibody functions: neutralize pathogens, opsonize pathogens, activate complement, activate innate immune cells.
    • B cells require activation through binding of antigen to their BCR which leads to BCR clustering + stimulation by a second signal (T helper cell).
    • BCRs develop diversity through: Gene segment rearrangement (VDJ recombination), junctional diversity (addition/deletion of ACTG), class switching (IgM -> IgX), affinity maturation (somatic hypermutation).

    T Cell Receptor

    • Heterodimers - composed of two proteins: α/β or γ/δ.
    • Each chain has a variable region that binds antigen and a constant region that associates with the membrane.
    • TCR assembled by genetic recombination and junctional diversity (like BCR): VJ for α chain, VDJ for β chain.
    • Do NOT undergo additional modifications.

    CD4/CD8 Co-Receptors

    • CTLs and Th cells have different functions and look at differing MHC molecules.
    • Naive T cells start as double positive cells (CD4 +CD8+).
    • During maturation cells choose a lineage: CD8: Killer T Cells – bind MHC class I, CD4: Helper T cells – bind MHC class II.
    • Differing structure.

    T Cells

    • Traditional T cells: >95% of T cells, α/β TCR, CD4 or CD8 co-receptors.
    • Non-traditional T cells: γ/δ TCR, No CD4 or CD8, most of their biology is unclear.

    How do naïve T cells become effector T cells?

    • Naïve T cells circulate in the blood and lymph.
    • Interact with antigen-presenting cells (APCs) in secondary lymphoid tissues that present a variety of peptides on MHC molecules: Dendritic cells, macrophages.
    • Interaction between T-cell receptor and MHC-peptide complex results in a signaling cascade and leads to T-cell activation.
    • Activation is followed by differentiation of T cell into an effector T cell.

    TCR Binding and MHC Antigen Presentation

    • Recognize presented antigen – must be in complex with MHC molecules.
    • TCR binds both antigen AND MHC molecule.
    • Class I and Class II MHC Molecules present different antigens to T cells: CD8 (CTL): MHC I, CD4 (T helper cell): MHC II.

    Class I MHC

    • Expressed by ALL cells.
    • Closed binding groove – bind end amino acids.
    • Peptide must be 8-9 amino acids.
    • Present intracellular peptide fragments.
    • Must complex with β2-microglobulin.
    • Displays “chopped up” endogenous proteins: “Self” proteins + viral proteins.
    • Allows hidden epitopes to be detected.
    • Killer T cells inspect MHC I looking for antigens.

    Class II MHC

    • Expressed only by antigen presenting cells (DCs, macrophages, B cells).
    • Open binding groove – binds middle amino acids.
    • Binds larger peptides (13-25 amino acids).
    • Present extracellular peptides (exogenous).
    • Present antigen to T helper cells, naïve T cells.
    • Two key system again required to set off T cell proliferation.

    Antigen Loading onto MHC

    • Class I – Endogenous Protein: Present ordinary cellular proteins, proteins encoded by microbes that have infected cells, “Billboard of proteins in the cell”.
    • Inspected by CTLs for non-self antigens.
    • Expressed by “ordinary” cells and antigen-presenting cells.

    Antigen Loading onto MHC

    • Class II – Exogenous Protein: Present proteins from the extracellular space.
    • “Billboard for what’s happening outside the cell.”
    • Inspected by T helper cells for activation.
    • Expressed by antigen presenting cells.

    Which MHC molecule(s) do DCs use to present antigens?

    • DCs use Class I MHC + endogenous peptides, Class II MHC + exogenous peptides, Class II MHC + endogenous peptides (not normal).

    How do APCs present antigens (pathogens/cancer) that do not infect APCs to CD8 T cells?

    • DCs present antigen to CD8 T cells through cross-presentation:
      • Dendritic cells can take up antigens from the extracellular space, process them, and then present them on MHC I to CD8 T cells.

    Tolerance of Self

    • “Negative Selection”: CD4+CD8+ T cells in the thymus are presented antigens by cTECs: Do you recognize any of the self-peptides displayed by the MHC molecules? Yes -> Die! No -> Live!.
    • mTECs (medullary thymic epithelial cells) digest their innards and display proteins.
    • Have TF (AIRE) that expresses tissue-specific proteins.
    • Thymic dendritic cells (TDCs) get antigens from the environment and are “given” antigens from mTECs.

    T Cell Selection Process

      1. Positive selection: ensures that developing T cells can recognize MHC molecules.
      1. Negative selection: eliminates T cells that recognize self-antigens.

    B Cells go through selection as well

    • Step 1: Check for functional BCR.
    • Step 2: Selection against self antigens.

    TCR Signaling

    • TCRs have short intracellular domains (like BCR).
    • Use CD3 to signal: Complex of 4 proteins (γ, δ, ε, ζ), have signaling motifs.
    • TCRs require clustering for activation.
    • T cells also use co-receptors for antigen recognition/signaling.
    • T cells require co-stimulation for full activation.

    TCR Activation

    • Step 1: Binding of antigen + MHC molecule by TCR + CD coreceptor.
    • Step 2: Co-stimulation: CD28 on T cells binds B7 on antigen-presenting cell, TCR + CD4 + CD28 = immunological synapse.
    • Step 3: Release of IL-2 leads to clonal expansion.

    Activation of Helper T Cells (CD4)

    • Produce cytokines to direct the immune response: Different Th cells produce different subsets of cytokines (Th1, Th2, Th17, Th1).
    • Positive feedback with cytokine secretion creates more Th.
    • DCs give cues on which cytokine to produce: What kind of invader are we dealing with? Where are they located?
    • DCs use PRRs and cytokine receptors to identify who/where.
    • Co-stimulatory molecules on DC informs Th cells.

    Production of Th1 Helper T Cells

    • DCs coming from bacterial/viral infections produce IL-12 -> Th1.
    • Th1 functions: Activates Macrophages and NK Cells, Restimulates Macrophages, B cells->IgG3, Growth factor for CTLs, NK cells, Th1.

    Production of Th2 Helper T Cells

    • DCs from sites with parasites produce IL-4 -> Th2.
    • Th2 functions: Growth factor Th2, B cells and B cells -> IgE, B cells -> IgA, Produces mucus in intestine.

    Production of Tfh Helper T Cells

    • Activate B cells to produce antibodies in response to extracellular pathogens.
    • Interact with B cells in the germinal center.
    • Recognizes MHC class II on B cell.
    • Release IL-4/IL-21 to stimulate B cells.
    • T and B cell must recognize Linked Epitopes – epitopes on the same molecular complex (pathogen).

    Production of Th17 Helper T Cells

    • DCs fungal or extracellular bacterial infections produce TGFβ, IL-6, or IL-23 -> Th17.
    • Th17 functions: Recruits neutrophils to sites of infection, Th17 growth factor, B cells -> IgG3, IgA.

    Activation of CTL (CD8 T Cells)

    • Biology is still not completely clear.
    • Early in infection: 2-cell interaction: Antigen presentation on MHC I by DC (cross-presentation), co-stimulation by the same DC, faster to react but short-lived and limited killing and proliferation potential.
    • Later in infection: 3-cell interaction: Antigen presentation on MHC I by DC, "Help" from T helper cell, proliferate robustly, kill efficiently, can become memory T cells.
    • Potentially possible through DC “licensing” or chemokine secretion.

    CD8 Effector T Cells (CTLs)

    • CTLs recognize pathogen on MHC class I on infected cells.
    • Carry lytic granules filled with cytotoxins: Perforin, Granzyme B.

    CD8 Effector T Cells (CTLs)

    • Induce apoptosis via: Pores in target cell membrane (lytic granules), Fas ligand expression (binds Fas on target cells).
    • Must kill cells without releasing cell contents.
    • Also produce IFNγ which upregulates MHC class I expression.

    CD8 Regulatory T cells (Tregs)

    • Restrains the immune response, maintains tolerance to self-antigens, prevents autoimmunity and allergies.
    • Induced by TGFβ.
    • Secrete IL-10 and TGFβ: IL-10 reduces APCs’ PRRs, IL-10 reduces APC expression of B7, IL-10 reduces T cell proliferation and CTL killing.

    Shutting Down Cellular Immunity

    • Checkpoint proteins: B7 has competitive binder (CTLA-4) – outcompetes CD28 and shuts down T cell activation, PD-1 expressed on T cells following activation, PD-1 binding PD-L1 inhibits T cell function.
    • Peripheral Tolerance: T cells with antigen but no co-stimulation = anergy.
    • Activation-Induced Cell Death: T cells that are re-activated over and over become sensitive to ligation of their Fas proteins by FasL on other T cells – apoptosis.

    Immunological Memory

    • B cell memory: Long-lived plasma cells: reside in bone marrow and continually produce low levels of antibodies.
    • B cell memory: Central memory B cell: reside in secondary lymphoid tissue and slowly proliferate to replace long-lived plasma cells that die.
    • Most have class switched and undergone affinity maturation = best of the best.

    Immunological Memory

    • T Cell memory: Tissue-resident memory T cells: were effector T cells but remain in tissues near site of infection.
    • T Cell memory: Effector memory T cells: circulate through blood/lymph.
    • T Cell memory: Central memory T cells: reside in secondary lymphoid organs, move out to tissues upon attack.
    • Th1, Th2, Th17 have long memories.

    Review: B Cells vs. T Cells

    • B Cells: Originate and mature in bone marrow, circulate in lymphatics until activated, become activated in lymph node, perform effector functions in lymph nodes and spleen.
    • T Cells: Originate in bone marrow, mature in thymus, circulate in lymphatics until activated, become activated in lymph node, perform effector functions in peripheral tissues (Th1, Th2, CTL) and lymph nodes (Tfh).

    Review – Receptor Diversity generated during development of BCR/TCR

    • B Cells: Generate BCR through VDJ recombination, junctional diversity, BCR matures through class switching, affinity maturation.
    • T Cells: Generates TCR through VDJ recombination, junctional diversity.
    • T Cells also have CD4/CD8 co-receptors.
    • B cells: Have short transmembrane regions – use Igα and Igβ to signal.
    • T cells: Have short transmembrane region – use CD3 to signal.

    BCR/TCR Development

    • Cells that bind self-molecules are deleted: tolerance.
    • Antigens on microbes bind a pre-existing pool of BCRs and TCRs.
    • Cells that bind these antigens are selected and expanded (clonal expansion).

    Review: B Cells vs. T Cells

    • B Cells: Bind free (opsonized) antigen and antigen on follicular dendritic cells, bind native antigens: folded proteins, carbohydrates, lipids.
    • T Cells: Bind presented antigen on MHC molecules found on APCs (MHC II) and all cells (MHC I), bind small linear peptide antigens.

    Review: B Cells vs. T Cells

    • B Cells: Activation requires co-stimulation: T cells (Th cells), other “danger” signals, affinity maturation requires Tfh binding.
    • T Cells: Activation requires co-stimulation: Activated dendritic cells, B7/CD28, Activity requires re-activation by antigen binding (macrophages/B cells for CD4 T cells).
    • B Cells: B cells produce antibodies which: Neutralize pathogens, Activate complement, Activate innate immune cells, Opsonize pathogens.
    • T Cells: T cells kill pathogens and help other cells kill pathogens: CD8: CTL – kills infected cels and eliminates infectious reservoir, CD4: Th cells – secrete cytokines to activate other immune cells.

    CD4 vs CD8

    • The type of infection determines which CD4 subset is made.

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