Cell-Mediated Immunity Activation PDF

BIOM 611G, Medical Microbiology PCOM Georgia CELL-MEDIATED IMMUNITY–1: ACTIVATION OF + + CD4 AND CD8 T...

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  Cellular and Molecular Immunology, 10th Ed., Abbas LEARNING OBJECTIVES 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 BETWEEN THE Distinguish between DIFFERENT naïve, effector and ‘CLASSES’ memory lymphocytes 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 HOW DO recirculation LYMPHOCYTES Identify MOVE AROUND? cell adhesion molecules that mediate lymphocyte extravasation 5 LYMPHOCYTE (RE)CIRCULATION ▪ Naïve lymphocytes circulate between secondary lymphoid tissues via lymphatics & blood ▪ Memory cells acquire ability to enter tissues 6 DCS CAPTURE & CARRY AGS TO LNS 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 on T cell::on endothelial cell of HEV 1. L-selectin::L selectin ligand 2. LFA-1::ICAM-1 3. CCR7::CCL19 or CCL21 9  HEV INTERACTION: A CLOSER LOOK ▪ 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 ▪ 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 TCR LOOK LIKE Diagram and label AND WHAT molecules involved in the T cell antigen OTHER receptor complex MOLECULES MUST ASSOCIATE? 12  TCR COMPLEX ▪ Cell-surface expression + signaling subunits ▪ TCRαβ heterodimer + 6 signaling chains: ▪ 2ε, 1δ, 1γ = CD3 ▪ homodimer of ζ 13 Adapted from: Fig 7.9 Janeways’s Immnuobiology, 10ed.  Describe cellular and molecular interactions HOW DO T between CD4+ T cell and a dendritic cell CELLS a) b) CD8+ T cell and a dendritic cell INTERACT Discuss key role of co-stimulatory signals WITH DCS IN provided by the CD28: B7.1/B7.2 (CD80/86) interaction and outcome if THE LN? these signals are not received by the T cell 14  STEPS IN THE ACTIVATION OF T LYMPHOCYTES (OVERVIEW) 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 3 SIGNAL REQUIRED TO Immunologic Synapse ACTIVATE T CELLS & 🡪 DIFFERENTIATION 1.Interaction of TCR with MHC-antigen ▪ Adhesion molecules stabilize the interaction of TCR with MHC-peptide complex 2. Co-stimulation ▪ Interaction with co-stimulatory molecules 3. Cytokines 16 QUICK LOOK: LIGAND-RECEPTOR PAIRS INVOLVED IN T CELL ACTIVATION AND DOWN-REGULATION 17 SIGNAL 1: INTERACTION OF TCR WITH MHC-ANTIGEN ROLE OF ADHESION MOLECULES IN T CELL ACTIVATION 18 Increased avidity binding SIGNAL 2: CO-STIMULATION ROLE IN T CELL ACTIVATION 19 T CELL ANERGY Functional inactivation of T cells that occurs 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 21 CAN ALSO BE ACTIVATED BY SUPERANTIGE NS 22 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  PROTEINS PRODUCED PROTEINS OF THE BY B7 & CD28 FAMILIES ANTIGEN-STIMULATED T CELLS & ROLE 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+ ▪ 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  WHAT Distinguish between DRIVES CD4+ cytokines and transcription factors T HELPER that promote differentiation of an CELLS TO activated T cell into a Th1,Th2 or Th17 cell DIFFERENTIA TE? 26 DEVELOPMENT OF CD4 CELL SUBSETS INVOLVES SPECIFIC CYTOKINES AND TRANSCRIPTION FACTORS T-dependent area in secondary lymphoid tissue 27  ONCE PART 2 Describe ACTIVATED, process of lymphocyte HOW DO T recirculation CELLS KNOW Identify WHERE THEY cell adhesion SHOULD molecules that MIGRATE TO mediate lymphocyte extravasation AND HOW DOES IT HAPPEN? 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 ▪ 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 ▪ Ex: hyaluronic acid and fibronectin 🡪 mediates firm T cell adherence to near Ag ▪ 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 Effector Th2 cells (not shown) recruit eosinophils, which destroy helminthic parasites and mediate allergic responses. 33 MIGRATION OF NAIVE T cell homing: Naive T cells home to lymph nodes as a result of L-selectin, integrin, and chemokine receptor CCR7 binding to their ligands on high endothelial AND EFFECTOR T venules (HEVs). 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 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 signal 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 transcription 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 host cells? 8. Why do differentiated effector T cells (which have been activated by antigen) migrate preferentially to tissues that are sites 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 killing 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