T cell Effector Responses PDF 2023

T cell Effector Responses Dr Allison Imrie Learning Objectives To understand and be able to explain: How T cells are activated: the costimulatory molecules the cytokines that control this process function of antigen presenting cells The role of T cells in adaptive immune T cell subsets and their fun...

T cell Effector Responses Dr Allison Imrie Learning Objectives To understand and be able to explain: How T cells are activated: the costimulatory molecules the cytokines that control this process function of antigen presenting cells The role of T cells in adaptive immune T cell subsets and their function T cell development: naïve and effector cells Naïve T cells: T cell has not previously encountered its cognate antigen Antigen is brought to lymph node by dendritic cell that has sampled antigen in periphery Naïve T cell that encounters cognate antigen is activated and undergoes clonal expansion, differentiates into effector or memory cells Effector T cells: Enter circulation and traffic to sites of infection in peripheral tissues Effector cells that encounter antigen in the periphery are further activated to mediate their effector functions Activation and movement of T cells is mediated by cytokines and chemokines Lymphocytes in the blood enter lymphoid tissue by crossing the walls of high endothelial venules CCL21 is expressed by HEV and stromal cells of lymphoid tissues and binds CCR7 on naïve T cells Contact of naïve T cells with CCL21 in the HEV causes the integrin LFA-1 on the naïve T cell to become activated, increasing its affinity for ICAM-1 ICAM-1 is only expressed on HEV of peripheral lymphoid tissues (in the absence of inflammation) Antigen is transported to lymphoid organs by dendritic cells B7-expressing DC stimulate naïve T cells Naïve T cells encounter antigen during their recirculation through peripheral lymph nodes Naïve T cells enter lymph nodes from arterial blood via specialized endothelial cells called high endothelial venues (HEV) T cells migrate into paracortical areas where they encounter dendritic cells T cells that do not encounter cognate antigen (green) leave node via lymphatics and return to circulation T cells that encounter cognate antigen (blue) become activated to proliferate into effector cells. They lose ability to exit lymph node After a few days effector cells regain ability to leave nodes and leave via efferent lymphatics and enter circulation Transient adhesive interactions between naïve T cells and dendritic cells are stabilized by recognition of specific antigen DC coupled to naïve antigen-specific T cell T cell receives signal to proliferate and differentiate Proliferated progeny cells = clones Stellate DC maintains contact with all clones = ‘nursery’ By five days after arrival of antigen in lymph nodes (via mature dendritic cells that have encountered antigen in the periphery, processed this antigen and presented to T cells in context of MHC molecules), activated effector T cells leave the node via efferent lymphatics All naïve t cells specific for a particular antigen can be trapped by that antigen (presented via DC that have trafficked to node) in node within 2 days 1) Antigen presentation: MHC/peptide to TCR MHC Class I/peptide to CD8+ T cell MHC Class II/peptide to CD4+ T cell 2) Co-stimulatory molecules CD28 on T cell to B7 (CD80/CD86) on DC CTLA-4 on T cell to CD80/CD86 on DC: for homeostasis 3) Cytokines T cell proliferation: IL-2 T cell lineage differentiation: cytokines produced by APC, mostly DC Variation in signal 3 causes naïve T cells to acquire several distinct types of effector function Subsets of CD4+ effector T cells are specialized to provide help for different classes of pathogens CD8+ Cytotoxic T lymphocytes( CTL) are selective and serial killers of target cells at sites of infection A pore is created in target cell by CTL perforin, granzymes Granzymes delivered through pore induce caspasedependent apoptosis pathways Most CD8+ T cell responses require help from CD4+ T cells CD8+ T cells recognizing antigen on weakly costimulatory cells may become activated only in the presence of CD4+ T cells interacting with the same APC ACP stimulates effector CD4+ T cell to induce expression of CD40L and IL-2 Effector CD4+ T cell recognises antigen on the APC and is triggered to induce increased levels of co-stimulatory activity on the APC: increased B7 and expression of 4-IBBL 4IBBL ligates 4-IBB (CD137) on CD8+ T cell – this enhances activation of CTL The CD4+ T cell also produces IL-2 that drives proliferation of CD8+ T cells TCR ligation with MHC/peptide complex in absence of CD28/B7 co-stimulation induces anergy: a state of unresponsiveness that is irreversible Contraction and re-establishment of homeostasis: role of CTLA-4 Binding of B7 to CTLA-4 inhibits T cell function. Anti–CTLA-4 antibodies block CTLA-4 binding and prevent inhibition of T cell function Co-stimulation is not required for recognition of antigen at infection site Development and function of TH1 T cells Classical macrophage activation by TH1 T cells Development and function of TH2 T cells TH2 cytokines inhibit classical macrophage activation and stimulate the alternative pathway of macrophage activation Development and function of TH17 T cells Regulatory T cells Treg Suppress and prevent immune responses eg. to self antigens: maintains tolerance Follicular helper T cells and the differentiation program of B lymphocytes In the presence of IL-6 CD4+ T cells differentiate into T FH cells that help B cells in the germinal centre reaction Polarised cytokine responses in disease pathogenesis: example of tuberculoid and lepromatous leprosy Decline of immune response Once immune response is over, system must return to steady state – homeostasis Once infection is cleared, cells are deprived of stimuli and survival signals Cells die of apoptosis Response subsides within 1-2 weeks after infection is eradicated Pool of memory cells remains Summary