Cell-Mediated Immunity Activation of CD4+ and CD8+ T Cells PDF

BIOM 611G, Medical Microbiology PCOM Georgia CELL-MEDIATED IMMUNITY–1: ACTIVATION OF CD4 AND CD8 T CELLS + + Valerie E. Cadet, PhD Assistant Dean of Health Equity Int...

BIOM 611G, Medical Microbiology PCOM Georgia CELL-MEDIATED IMMUNITY–1: ACTIVATION OF CD4 AND CD8 T CELLS + + Valerie E. Cadet, PhD Assistant Dean of Health Equity Integration Professor of Microbiology and Immunology BMS1 & BMS2 Department of Biomedical Sciences January 16, 2025  LEARNING OBJECTIVES Cellular and Molecular Immunology, 10th Ed., Abbas Chapter 9: Activation of T Lymphocytes Through the study of this content and recommended reading, the successful student will be able to……. 1. Distinguish between naïve, effector and memory lymphocytes. 2. Describe the process of lymphocyte recirculation and identify the cell adhesion molecules that mediate lymphocyte extravasation. 3. Diagram and label the molecules involved in the T cell antigen receptor complex. 4. Describe the cellular and molecular interactions between: 1. CD4+ T cell and a dendritic cell 2. CD8+ T cell and dendritic cell 5. Describe how the interactions between immune cells result in the activation of the T cells 6. Discuss the key role of co-stimulatory signals provided by the CD28: CD80/86 interaction and the outcome if the T cell does not receive these signals. 7. Distinguish between the cytokines and transcription factors that promote differentiation of an activated T cell into a Th1, Th2 or Th17 cell. 2  WHAT’S THE DIFFERENCE Distinguish between BETWEEN THE naïve, effector and memory lymphocytes DIFFERENT ‘CLASSES’ OF LYMPHOCYTES? 3 THE DISTINCTION BETWEEN LYMPHOCYTE STATUS Naïve ▪ T/B cell not yet encountered antigen to which they are specific Effector ▪ T/B cell specifically activated & differentiated to carry out immune functions targeted towards specific antigen Memory ▪ T/B cell that retains ability to rapidly reactivate after re-exposure to antigen it has encountered before → into effector cell ▪ Basis for development of immunity after infection or vaccination 4  PART 1 Describe process of lymphocyte recirculation HOW DO LYMPHOCYTES Identify MOVE AROUND? cell adhesion molecules that mediate lymphocyte extravasation 5 LYMPHOCYTE (RE)CIRCULATION Y arehave me a from venous circulation to mucosal creas LN, PleaT ▪ Naïve lymphocytes , MALT, e +c circulate between secondary lymphoid tissues via lymphatics & blood ▪ Memory cells acquire > ↳ability to enter tissues T can cells become & B cells memory cells i invote 6 DCS CAPTURE & CARRY AGS TO LNS activateb presenting antigen a & inliving 7  T CELL ENTERS LN AND MEET ITS ANTIGEN ON DC Non-specific, low-affinity interaction via adhesion molecules ▪ If the T cell ‘sees’ it’s specific Ag➔ high affinity integrin binding ensues ➔T cell activation 8 HOMING OF NAIVE T CELLS INTO LN naisetellenterin a - (HEY) i on T cell::on endothelial cell of HEV 1. L-selectin::L selectin ligand 2. LFA-1::ICAM-1 - can & bird w/ integrin like stop T cell movement, LEA-I 3. CCR7::CCL19 or CCL21 finity it : if right antigen , change come & turn to a affinity binding 9  in blood (venous circulate HEV INTERACTION: A CLOSER LOOK ↑ ↑ T cells enter via HEY, while antigens & d enter vin afferent circulate lymphatic vessel the lymphatics ▪ T cells travel through the HEV into cortical region of lymph node ▪ Pass through tissue, examine APC ▪ IF it sees it’s Ag➔ activate, proliferate, differentiate ▪ IF it doesn’t see it’s Ag ➔ recirculates out via efferent lymphatics ➔thoracic duct ➔ venous circulation 10 MECHANISM FOR T CELL TRAVERSING THE HEVS ▪ Controlled by weak contacts made by cell surface interactions between L-selectin and carbohydrate selectin ligands (GlyCAM-1 and CD34) ▪ Process also influenced by chemokines (CCL19/21 binding CCR7)➔integrin activation ↳ leads to conf changed ↑ affinity binding ▪ Stable adhesion due to (LFA-1) integrin binding (ICAM-1) ▪ Homing of T cells into draining lymph nodes significantly enhanced at sites of acute inflammation ▪ Egress via efferent lymphatics transiently reduced ▪ Probably due to cytokines produced as part of the innate immune response (interferons, IFNs) 11  WHAT DOES THE Diagram and label TCR LOOK LIKE AND molecules involved in WHAT OTHER the T cell antigen MOLECULES MUST receptor complex ASSOCIATE? 12  TCR COMPLEX ▪ Cell-surface expression + signaling subunits epsilon delta gamen ▪ TCRαβ heterodimer + 6 signaling chains: ▪ 2ε, 1δ, 1γ = CD3 ▪ homodimer of ζ (ze + a) TCR = &B ! +CD+ & Y TCR complex = (ap) the D or CDF ! " 13 Adapted from: Fig 7.9 Janeways’s Immnuobiology, 10ed.  Describe cellular and molecular interactions between HOW DO T CELLS a) CD4+ T cell and a dendritic cell b) CD8+ T cell and a dendritic cell INTERACT WITH DCS Discuss IN THE LN? key role of co-stimulatory signals provided by the CD28: B7.1/B7.2 -ak (CD80/86) interaction and outcome if these signals are not received by the T cell 14  STEPS IN THE ACTIVATION OF T LYMPHOCYTES (OVERVIEW) lands to lymphocyte X proliferation ; lymphocytes proliferate only ve/ cytokines cantocrine 1. Naive T cells recognize MHC–associated peptide antigens displayed on APCs and other signals. 2. T cells respond by producing cytokines, such as IL-2, and expressing receptors for these cytokines, leading to an autocrine pathway of cell proliferation. 3. Result is expansion of the clone of T cells that are specific for the antigen. 4. Progeny differentiate into effector cells, serving various functions in CMI, and memory cells, which survive for long periods. 15  Immunologic Synapse 3 SIGNAL REQUIRED TO ACTIVATE T CELLS & → DIFFERENTIATION & aka. 1. Interaction of TCR with MHC-antigen ! ▪ Adhesion molecules stabilize the interaction of TCR with MHC-peptide complex ⑭ 2. Co-stimulation ▪ Interaction with co-stimulatory molecules 3. Cytokines 16 QUICK LOOK: LIGAND-RECEPTOR PAIRS INVOLVED IN T CELL ACTIVATION AND DOWN-REGULATION red TC see-APC : ↑ · ⑤ * ⑪ 17 SIGNAL 1: INTERACTION OF TCR WITH MHC-ANTIGEN ROLE OF ADHESION MOLECULES IN T CELL ACTIVATION ! G & , ① ⑥ & - - 18 Increased avidity binding & SIGNAL 2: CO-STIMULATION ROLE IN T CELL ACTIVATION a 19 T CELL ANERGY Functional inactivation of T cells that occurs n when cells recognize antigens without adequate levels of the costimulators (second signals) needed for full T cell activation ▪ Antigen presented by costimulator- expressing APCs induces normal T cell response ▪ If T cell recognizes antigen without strong costimulation (B7.1/2 aka CD80/86- deficient APC), TCR may lose ability to deliver activating signals ▪ If T cell engages inhibitory receptors (CTLA-4/PD-1) activation blocked 20 Basic Immunology Fig. 9-3 SIGNAL 3: CYTOKINES IN T CELL ACTIVATION I L- 2 is what helps alway proliferation ~ Signal I >sisn2not on a Signal 3 eitet es #L - 2 ↑Tr pick ut an additional chain of that receptor ; that IL2-R becomes ↑Raftereirst bit' of IL-2 21 SIGNAL 3: CYTOKINES ROLE OF IL-2 AND IL-2R IN T CELL PROLIFERATION Principal functions ▪ Stimulate survival and proliferation of T cells → resulting in increase in number of antigen-specific T cells ▪ Essential for maintenance of regulatory T cells → controlling immune responses 23  CD4+ T CELLS CAN ALSO BE ACTIVATED BY SUPERANTIGENS >comla - them hold on tightly 22 PROTEINS OF THE B7 & PROTEINS PRODUCED BY ANTIGEN- CD28 FAMILIES programmed death-ligand & look similar to B STIMULATED T CELLS & ROLE ↑ Brecepto a i ~ & - Dinin ↳ ↑ " anergy if = this either become does not anergic occur or , then inhibited[or it will deleted) 24 A NOTE ON CLONAL EXPANSION AND CONTRACTION ▪ Expansion: ▪ Pre-Ag exposure, frequency of naive T cells specific for any antigen → 1 in 105 to 106 lymphocytes. ▪ Post-microbial Ag exposure, frequency of T cells specific for that microbe increases ▪ CD8+ → 1 in 3 CD8+ T lymphocytes, representing a >50,000- fold expansion of Ag-specific CD8+ dinin ▪ CD4+ cells → 1 in 100 Ag-specific CD4+ lymphocytes - ▪ Contraction is essential to reduce potential for T cell exhaustion and excessive immune-mediated tissue damage. ▪ Associated with appearance of PD-1 and CTLA-4 on T cells 25  Distinguish between WHAT DRIVES cytokines and transcription factors CD4+ T HELPER that promote differentiation of an CELLS TO activated T cell into a Th1,Th2 or Th17 cell DIFFERENTIATE? 26  cytokines Thoaknot ! secretes transcription DEVELOPMENT OF CD4 CELL SUBSETS INVOLVES SPECIFIC factors CYTOKINES AND TRANSCRIPTION FACTORS will present antigen T-dependent area in secondary lymphoid tissue permute inflammatory - response ; promote newtrophils & import net for 27 extracellular infections : smaller inf , fungi  PART 2 Describe process of lymphocyte ONCE ACTIVATED, HOW recirculation DO T CELLS KNOW Identify WHERE THEY SHOULD cell adhesion MIGRATE TO AND HOW molecules that DOES IT HAPPEN? mediate lymphocyte extravasation 28  HOMING OF EFFECTOR T CELLS TO SITE OF INFECTION on T cell::on endothelial cell of HEV 1. E- and P-selectin ligand::E- or P- selectin 2. LFA-1 or VLA-4::ICAM-1 or VCAM-1 3. CXCR3 & others::CXCL10 & others ▪ Homing is independent of Ag recognition ▪ Lymphocytes that recognize Ags preferentially retained and activated at the site Don’t Forget: ▪ Follicular helper T (Tfh) ▪ Express CXCR5 ➔ lymphoid follicles ▪ Stimulate resident B cells 29  THE ROLE OF S1P IN EFFECTOR CELL EGRESS when a naive T cell in the lymph node is activated by an antigen, it temporarily loses its ability to leave the lymph node. this happens because a protein called S1PR1, which helps cells follow a chemical signal (S1P) to exit is SUPPRESSED. interferons and antigen activation increases another protein, CD69, which blocks S1PR1 from reaching the cell surface; this sphingosine I keeps the T cells in the lymph node so they can multiply and become effector T cells, which takes a few days.. Phosphate ↑ once the T cells are ready, they stop making CD69, S1PR1 returns to the surfaceand they leave the lymph nodes to fight infections ▪ Levels of S1P are higher in blood and lymph than inside lymph nodes ▪ S1P binds to and induces internalization of its receptor ➔ expression of receptor on circulating naive T cells low ▪ If T cell doesn’t ‘see’ it’s antigen it leaves LN ▪ via efferent lymphatic vessels, following S1P gradient ➔ lymph ▪ If T cell ‘sees’ it’s antigen ➔ activation ▪ CD69 downregulates S1P receptor ▪ Clonal expansion and differentiation ▪ S1P receptor re=expressed on T cell ▪ Cells lose expression of L-selectin and CCR7 ➔ draining lymph ➔ circulation as 30 differentiated effector cell WHAT HAPPENS IF S1P IS INHIBITED? Clinical Correlation ▪ Drug fingolimod ▪ Binds S1P receptor ▪ Blocks T cells exit from LNs ▪ Approved for treatment of the inflammatory disease multiple sclerosis (MS) 31 Importance of the S1P pathway ACTIVATED T CELLS GET RE-ACTIVATED ▪ Effector T cells leave circulation and specifically recognize microbial antigen presented by local tissue APCs ➔ reactivation and effector mechanisms, ultimately to killing of microbe in APC ▪ Upon reactivation ▪ Expression of VLA-4 integrin increases ➔ bind to extracellular matrix molecules ➔ mediates firm T cell adherence to near Ag ▪ Ex: hyaluronic acid and fibronectin ▪ Selective retention ➔ accumulation of more and more T cells specific for microbial Ags at site of infection 32  OUTCOME OF T CELL REACTIVATION AT SITE OF INFECTION secrates Effector Th2 cells (not shown) IFN - & Y & I2-21 ? recruit eosinophils, which destroy helminthic parasites and mediate J J allergic responses. 33  T cell homing: Naive T cells home to lymph nodes as a MIGRATION OF NAIVE AND result of L-selectin, integrin, and chemokine receptor CCR7 binding to their ligands on high endothelial venules (HEVs). EFFECTOR T CELLS ALL TOGETHER T cell exiting of lymph nodes: Activated T cells, including the majority of effector cells, home to sites of infection in peripheral tissues Follicular helper T (Tfh) (not shown) are effector cells that remain in lymphoid organs due to expressing chemokine receptor CXCR5 (ligand=CXCL13) which draws them into lymphoid follicles. They interact with resident B lymphocytes there. 34 DEVELOPMENT OF IMMUNOLOGICAL MEMORY IS SIMILAR FOR BOTH B & T CELLS 35 CHARACTERISTICS OF MEMORY T CELLS 1. Express increased levels of anti-apoptotic proteins 2. Respond more rapidly to antigen stimulation than naive cells specific for same antigen 3. Are greater in number than naive cells specific for same antigen 4. Able to migrate to peripheral tissues and respond to antigens at these sites 5. Undergo slow proliferation (self-renewing), contributing to long life span of memory pool 36 2 POPULATIONS OF MEMORY T CELLS EXIST Central memory T cells ▪ Express CCR7 and L-selectin → lymph nodes ▪ Have limited capacity to perform effector functions when they encounter Ag, but undergo brisk proliferative responses and generate many effector cells on Ag challenge ▪ Effector memory T cells ▪ Do not express CCR7 or L-selectin → peripheral sites, especially mucosal tissues ▪ On Ag stimulation, produce effector cytokines such as IFN-γ or rapidly become cytotoxic, but do not proliferate much ▪ Poised for rapid response to repeated exposure to a microbe, but complete eradication of infection may also require large numbers of effectors generated from the pool of central memory T cells 37 SUMMARY: INDUCTION AND EFFECTOR PHASES OF CMI ▪ Induction of response ▪ Naive CD4+ and CD8+ T cells recognize peptides derived from protein antigens and presented by dendritic cells (DCs) in peripheral lymphoid organs ▪ T cells are stimulated to proliferate and differentiate into effector cells, many which enter circulation ▪ Some of the activated CD4+ T cells remain in the lymph node, migrate into follicles, and help B cells to produce antibodies (shown in Fig. 5- 13) ▪ Migration of effector T cells and other leukocytes to site of antigen ▪ Effector T cells and other leukocytes migrate through blood vessels in peripheral tissues by binding to endothelial cells that have been activated by cytokines produced in response to infection in these tissues ▪ T cell effector functions (CMI-effector mechanisms lecture) ▪ CD4+ T cells recruit and activate phagocytes to destroy microbes; recruit eosinophils and help B cells produce antibodies ▪ CD8+ CTLs kill infected cells 38 Figure 05-02 REMEMBER THE BIG PICTURE 39  QUESTIONS TO CONSIDER: CMI 1. What are the components of the TCR complex? Which of these components are responsible for antigen recognition and which for s ignal transduction? 2. What are some of the accessory molecules that T cells use to initiate their responses to antigens, and what are the functions of these molecules? 3. What is costimulation? What is the physiologic significance of costimulation? What are some of the ligand-receptor pairs that are involved in costimulation? 4. Summarize the links between antigen recognition, the major biochemical signaling pathways in T cells, and the production of t ranscription factors. 5. What is the principal growth factor for T cells? Why do antigen-specific T cells expand more than other ("bystander") T cells on exposure to an antigen? 6. What are the major subsets of CD4+ helper T cells, and how do they differ? 7. What signals are required to induce the responses of CD8+ T cells? What are the types of T lymphocyte -mediated immune reactions that eliminate microbes that are sequestered in the vesicles of phagocytes and microbes that live in the cytoplasm of infected hos t cells? 8. Why do differentiated effector T cells (which have been activated by antigen) migrate preferentially to tissues that are site s of infection and not to lymph nodes? 9. What are the mechanisms by which T cells activate macrophages, and what are the responses of macrophages that result in the k illing of ingested microbes? 10.What are the roles of TH1 and TH2 cells in defense against intracellular microbes and helminthic parasites? 11.How do CD8+ CTLs kill cells infected with viruses? 12.What are some of the mechanisms by which intracellular microbes resist the effector mechanisms of cell -mediated immunity? 40