T Cell Activation (PDF)

3/14/24 The Immune System Dr. Dalia Zakaria 1 Adaptive Immunity V Mechanisms of Lymphocytes Activation Activation of T Cells Textbook Reading: Chapter 5 2 1 3/14/24 What Do You Need to Learn? Components of the immune system (an overview) Components of the innate immune system Mechanisms of innate im...

3/14/24 The Immune System Dr. Dalia Zakaria 1 Adaptive Immunity V Mechanisms of Lymphocytes Activation Activation of T Cells Textbook Reading: Chapter 5 2 1 3/14/24 What Do You Need to Learn? Components of the immune system (an overview) Components of the innate immune system Mechanisms of innate immune responses Transition from innate to adaptive immune response Components of the adaptive immune system (lymphocytes and lymphatic system) How do lymphocytes recognize their specific antigens (development) and how do they distinguish between self and non-self molecules (maturation) Mechanisms of lymphocytes activation Effector mechanisms of the adaptive immune responses 3 Objectives After completing this module, you should understand the following: Types of receptors and coreceptors that take part in the activation of T cells The 2 main signals that are required to activate naïve T cells The importance of costimulation and the costimulatory molecules The steps of CD4+ and CD8+ activation and differentiation The different types of differentiated T cells and their functions Clonal expansion and the difference between the effector T cells and the memory T cells 4 2 3/14/24 Recognition of MHC-Antigen Complex 5 T cell receptor binding to its specific antigen (presented on MHC molecules) is important to activate naïve T cells But … This is not enough What else? 6 3 3/14/24 COSTIMULATION Is Essential APCs T cells Activation Co-stimulatory receptor (CD28) Must bind Co-stimulatory molecules (B7-1 or B7-2) 7 Activation of T cells without co-stimulation may lead to T cell deletion or the development of immune tolerance 8 4 3/14/24 Two signals are required to activate T cells during antigen presentation 9 T Cell-Antigen-APC Binding Signal 2: costimulatory receptor binding Signal 1: TCR binding to MHC CD4+ T cell receptor (TCR) Co-stimulatory receptor (CD28) Binds to Binds to MHC associated peptide antigens presented by APC Co-stimulators expressed by APCs (B7-1 or B7-2) APC 10 5 3/14/24 Two signals are required to activate T cells during antigen presentation Signals generated due to the engagement of antigen receptors and receptors for costimulators lead to the transcription of various genes, which encode cytokines, cytokine receptors, effector molecules, and proteins that control cell survival and cycling 11 T Cell-Antigen-APC Binding (Activation) T Cell Adhesion Molecule (Integrin) T Cell Receptor (TCR) Binds to MHC associated peptide antigens Expressed by APC The T cell receptor (TCR) recognizes MHC-associated peptide antigens Co-stimulatory Receptors (CD28) Binds to Co-stimulators expressed by APCs (B7-1 and B7-2) Binding of CD28 on T cells to B7 on the APCs generates signals in the T cells that work together with signals generated by TCR recognition CD4 or CD8 Co-receptors Binds to MHC II or MHC I (respectively) expressed by APC CD4 or CD8 coreceptors on T cells recognize MHC on the APC and help the TCR complex to deliver activating signals Binds to Integrin Ligand (ICAM) expressed by APC TCR bind to its antigen with low affinity. Binding is stabilized with adhesion molecules on the T cells that bind to ligands expressed on APCs 12 6 3/14/24 T Cell Receptors and Signaling Molecules Inhibitory Receptors 13 Role of Costimulators Molecules in T Cell Responses The full activation of T cells depends on the recognition of costimulators on APCs in addition to antigen The best-defined costimulators for T cells are two related proteins called B7-1 and B7-2 Their expression on APCs is increased when the APCs encounter microbes The requirement for costimulation ensures that naïve T lymphocytes are activated fully by microbial antigens and not by harmless foreign substances or by self antigens These B7 proteins are recognized by a receptor called CD28, which is expressed on most T cells The binding of CD28 on T cells to B7 on the APCs generates signals in the T cells that work together with signals generated by TCR recognition of antigen presented by MHC proteins on the same APCs 14 7 3/14/24 Inhibitory Receptors of T Cells Inhibitory receptors are critical for limiting and terminating immune responses Two important inhibitory receptors—CTLA-4 and PD-1—are structurally related to CD28 CTLA-4, like CD28, recognizes B7-1 (CD80) and B7-2 (CD86) on APCs, and PD-1 recognizes different but structurally related ligands on many cell types. CTLA-4 and PD-1 are also involved in inhibiting responses to some tumors and chronic viral infections These discoveries are the basis for the use of antibodies that block CTLA-4 or PD-1 to enhance immune responses to tumors in patients with cancer 15 Recognition of MHC-Antigen Complex and Costimulators Naive T cells have a low level of protein synthesis Antigen recognition activates several biochemical mechanisms that lead to T cell responses, including the activation of enzymes such as kinases, recruitment of adaptor proteins, and production of active transcription factors The synapse was first described as the site of delivery of activating signals from membrane receptors to the cell’s interior Some effector molecules and cytokines may be secreted through this region, ensuring that they do not diffuse away but are targeted to the APC 16 8 3/14/24 Recognition of MHC-Antigen Complex and Costimulators 17 Secretion of Cytokines and Expression of Cytokines Receptors In adaptive immunity, cytokines are secreted mainly by CD4+ effector cells which serve diverse roles in host defense IL-2 is produced within 2 hours after activation of CD4+ T cells which is associated with the expression of IL-2 receptor (IL-2R), thus rapidly enhancing the ability of T cells to bind and respond to IL-2 (autocrine effect) The principal functions of IL-2 (T cell growth factor) are to stimulate the survival and proliferation of T cells Stimulated CD8+ T cells do not secrete large amounts of IL-2 which may be provided by CD4+ helper T cells 18 9 3/14/24 Secretion of Cytokines and Expression of Cytokines Receptors Expression of high affinity IL-2R Clonal Expansion 19 CD4+ Helper T Cells Play a Role in the Activation of CD8+ Initiation of CD8+ T cell activation often requires cytosolic antigen (e.g., virus-infected or tumor cells) to be cross-presented by APCs When virus-infected cells are ingested by dendritic cells, the APC may present viral antigens from the cytosol in complex with class I MHC molecules and from vesicles in complex with class II MHC molecules Thus, both CD8+ T cells and CD4+ T cells specific for viral antigens are activated near one another CD4+ T cells may produce cytokines or membrane molecules that help to activate the CD8+ T cells This explains the defective CTL responses to many viruses in patients infected with HIV, which kills CD4+ but not CD8+ T cells 20 10 3/14/24 CD4+ Helper T Cells Play a Role in the Activation of CD8+ 21 APCs Express another Costimulatory Molecule (CD40) APC CD40 CD40L CD40L-CD40 binding T Cell Activation of APC to express more B7 costimulators and to secrete cytokines (e.g. IL-12) Interaction of CD40L expressed on an antigen-stimulated T cells with CD40 on DCs increases the expression of costimulators on these APCs and the production of T cell–stimulating cytokines (positive feedback) 22 11 3/14/24 COSTIMULATION Is Essential APCs T cells Activation Co-stimulatory receptor (CD28) Must bind Co-stimulatory molecules (B7-1 or B7-2) Enhance activation and differentiation Binds to CD40 L CD40 Binding activates APC to produce more cytokines such as IL-12 and more B7 stimulators 23 Role of Costimulation in T Cell Activation Agents that block B7:CD28 interactions are used in the treatment of rheumatoid arthritis Using antibodies to block CD40:CD40L interactions are being tested in inflammatory diseases 24 12 3/14/24 Differentiation of Activated T Cells CD4+ T cells Effector T helper cells Th1 Th2 Memory T helper cells CD8+ T cells Effector cytotoxic T cells Memory cytotoxic T cells Th17 Effector CD4+ T cells migrate to sites of infection, where their cytokines recruit other leukocytes that destroy the infectious agents Other differentiated CD4+ T cells remain in the lymphoid organs and migrate into lymphoid follicles, where they help B lymphocytes to produce antibodies (T follicular helper, Tfh) 25 Functions of Th1, Th2 and Th17 Cell Subsets (Cytokines Profile) 26 13 3/14/24 Differentiation of T Cells to Effector T Cells Differentiation is due to changes in gene expression, such as activation of genes encoding cytokines (CD4+ T cells) or cytotoxic proteins (CD8+ CTLs) It begins in concert with clonal expansion, and differentiated effector cells appear within 3 or 4 days after exposure to microbes The subsets of T cells that are distinguished by their cytokine profiles are named Th1, Th2, and Th17 many of which may leave the peripheral lymphoid organs and migrate to sites of infection, where their cytokines recruit other leukocytes that destroy the infectious agents Other differentiated CD4+ T cells migrate into lymphoid follicles, where they help B lymphocytes to produce antibodies CD40L is expressed on activated helper T cells in response to antigen recognition and costimulation and binds to its receptor, CD40, which is expressed mainly on macrophages, B lymphocytes, and dendritic cells to stimulate them 27 Differentiation of T Cells to Memory T Cells A fraction of antigen-activated T lymphocytes differentiates into long-lived memory cells which are induced by microbes when the infection return Factors determine whether the progeny of antigen-stimulated lymphocytes will differentiate into effector cells or memory cells are not fully understood Memory cells have several important characteristics: Survive after the infection is eradicated Certain cytokines, including IL-7 and IL-15 (produced by stromal cells in tissues) may keep memory cells alive They may be rapidly induced (only when encounter the antigen) to produce cytokines or kill infected cells 28 14 3/14/24 Clonal Expansion of T Cells The frequency of naive CD8+ T cells specific for any antigen is about 1 in 105 or 1 in 106 lymphocytes At the peak of some viral infections (within a week after infection) 10% - 20% (10000 folds) of lymphocytes in the lymphoid organs may be specific for that virus (doubling time of about 6 hours) In infections with complex microbes that contain many protein antigens, a majority of the expanded clones are specific for only a few, often less than five, immunodominant peptides of that microbe The expansion of CD4+ T cells appears to be 100-1000-fold less than that of CD8+ cells which may reflect differences in their functions CD8+ CTLs are effector cells that kill infected cells by direct contact, and many CTLs may be needed to kill large numbers of infected cells Each CD4+ effector cell secretes cytokines that activate many other effector cells, so a relatively small number of cytokine producers may be sufficient 29 Clonal Expansion of T Cells The expansion of CD4+ T cells appears to be 100-1000-fold less than that of CD8+ cells which may reflect differences in their functions 30 15 3/14/24 Activation, Proliferation and Differentiation of T Cells Recognition of MHC-antigen complex and costimulators (CD28:B7-1/B7-2 binding) T cell activation CD4+ secrete IL-2 and express high affinity IL-2R IL-2 binds to IL-2R (autocrine effect) which enhances survival and proliferation of T cells CD40L:CD40 binding Enhanced expression of B7 by APC Activation of APC to express cytokines (e.g. IL-12, depending on type of antigen) Differentiation of CD4+ and CD8+ into effector and memory helper and cytotoxic T cells 31 16