Transcript 7 T cell
ANTIGEN RECOGNITION BY T-CELLS REQUIRES PEPTIDE ANTIGENS AND ANTIGEN PRESENTING CELLS THAT EXPRESS MHC MOLECULES !! T II soluble Ag Native membrane Ag Cell surface MHCpeptide complex Peptide antigen Cell surface peptides APC APC APC No T-cell response T-cell response MHCI Expressed by all nucleated cells STRUCTURE OF CLASS I MHC MOLECULES PEPTIDE 2 3 1 2m ! ! MHCII ! ! Expressed by professional antigen presenting cells Macrophage, dendritic cell, B cell STRUCTURE OF CLASS II MHC MOLECULES PEPTIDE 1 1 2 2 RECOGNITION OF EXOGENOUS AND ENDOGENOUS ANTIGENES BY T-LYMPHOCYTES ! ! Tc Th TCR TCR Peptide Peptide MHCI MHCII Exogenous Ag Endogenous Ag APC Peptides of endogenous proteins (virus, tumor) bind to class I MHC molecules presented to cytotoxic T cells Peptides of exogenous proteins (toxin, bacteria, allergen) bind to class II MHC molecules presented to helper T cells B cell epitop T cell epitop B cells recognize: T cells recognize: proteins polysaccharides lipids DNS steroids drugs, etc peptides (8-23 amino acid) Tissue or soluble antigens ! ! only when these peptides are presented by MHC molecules on APC cells TCR !! T cell receptor (TCR) The TCR, which recognizes peptide antigens displayed by MHC molecules BCR V s VL sH s s s s s C sH1 s CLs s s s s s s s s s ss ss CH2ss ss CH3ss s s : •membrane-bound heterodimer composed of an α chain and a β chainm, each chain containing one variable (V) region and one constant (C) region Both the α chain and the β chain of the TCR participate in specific recognition of MHC molecules and bound peptides s CD3 jeltovábbítás CD3 jeltovábbítás TCR is similar to BCR, but: TCRs only function as membrane receptors B cell TCR T cell !! Plasma cell TCR has single antigen recognition unit cells B and TTcell functions T cell migration and activation A T-cell precursors migrate from the bone marrow to thymus Dendritic cells take up antigen in the tissues, migrate to peripheral lymphoid organs, and present foreign antigens to naive T cells. T cell response requires the DC-mediated antigen prezentation in the secondary lymphoid organs ! ANTIGEN RECOGNITION BY T-CELLS REQUIRES PEPTIDE ANTIGENS AND ANTIGEN PRESENTING CELLS THAT EXPRESS MHC MOLECULES !! T II soluble Ag Native membrane Ag Cell surface MHCpeptide complex Peptide antigen Cell surface peptides APC APC APC No T-cell response T-cell response CHARACTERISTICS OF T-CELL ANTIGEN RECOGNITION 1. The TCR is not able to interact directly with soluble or cell-bound antigen 2. T-cell activation can be induced by antigen in the presence of acessory cells, only 3. T-cells recognize virus-infected cells ACCESSORY CELL ANTIGEN BINDING NO INTERACTION V T-CELL ACTIVATION C Antigen receptor B-CELL / T-CELL THE IMMUNOLOGICAL SYNAPSE APC T THE INTERACTION OF T CELLS AND ANTIGEN PRESENTING CELLS interaction recognition 1 2 3 4 5 6 stabilization 7 8 separation Negulescu P.A. et. al. Immunity 4: 421-430, 1996 (review) Phases of T cell response ! Effector functions of T cells: 1. cytotoxicity 2. citokine production Effector T cells Cytotoxic T cells Against Helper T cells intracellular intra and extracellular pathogens Antigen prezentation activates T cells, both cytotoxic and helper T cells require antigen presentation RECOGNITION OF EXOGENOUS AND ENDOGENOUS ANTIGENES BY T-LYMPHOCYTES ! ! Tc Th TCR TCR Peptide Peptide MHCI MHCII Exogenous Ag Endogenous Ag APC Peptides of endogenous proteins (virus, tumor) bind to class I MHC molecules presented to cytotoxic T cells Peptides of exogenous proteins (toxin, bacteria, allergen) bind to class II MHC molecules presented to helper T cells CITOTOXIC T LYMPHOCYTES cytotoxic T cells Infected or tumoric cells Cytotoxic T-cells KILLING OF INFECTED CELLS BY CTL Recognition by CTLs induces secretion of cytotoxins to the target cell KILLING OF TUMOR CELLS BY CTL Cytotoxic T lymphocytes recognize virus-infected or tumor cells Activated cytotoxic T-lymphocytes kill virus-infected or tumor cells PHYSIOLOGICAL AND PATHOLOGIC CELL DEATH Apoptotic signal Cell demage Apoptosis Necrosis DNS-ladder Inflammatory cytokines IL-1 TNFa IL-6 Macropha ge Granulocyte, macrophage APOPTOSIS Healthy cell Necrotic cell Late apoptotic cell Apoptotic cell HIGHLY REGULATED PROCESS 1. Induction 2. Excecution • Mitochondrial function • Electron transport • Oxidative phosphorylateion • ATP synthesis * Activation of caspases * Serine protease,calpain, proteasome * Redox potential * DNA degradation (endonuclease) MECHANISM OF CELLULAR KILLING BY CD8+ CYTOTOXIC T LYMPHOCYTES H2O, Ca++, ions Polymerized perforin Granzyme CYTOKINE RELEASE CD8 APOPTOSIS TCR MHC+ peptide ICE/CASPASE Crosslinking FasL Fas CD8+ T CELL TARGET CELL !! Activation of helper T cells results in cytokine production THE MOST IMPORTANT FEATURES OF CYTOKINES The most important mediators of indirect cell communication in the immune system („hormones” of the immune system). Act in low concentrations. Cytokines can affect in an autocrine way, in a paracrine way, or in an endocrine way pleiotropic effect. Cytokines can act by synergistic or antagonistic ways to each other. A given cell may by affected by many cytokines resulting in the same effect redundant effect. - The responsiveness of the given cell is based on the expression of cytokine-specific receptors. !! EFFECTOR CD4+ HELPER T LYMPHOCYTES SECRETE DIFFERENT CYTOKINES Th1 Th0 IFNγ Th2 IL-4 IL-4, IL-5, IL-10 IFNγ, IL-2, TNF-β/LT Inflammatory cytokines Anti-inflammatory cytokines CELLULAR IMMUNE RESPONSE HUMORAL IMMUNE RESPONSE The three types of effector T cell produce distinct sets of effector molecules. TH1 sejtek Effector function of TH1 cells Activation of CD8 cytotoxic T cells Makrofág aktiváció, baktérium ölés Krónikusan fertőzött makrofágok elpusztítása, baktérium pusztítás T sejt osztódás, effektor sejtek Makrofág differenciáció a csontvelőben Endotél aktiváció, makrofág migráció Makrofág akkumuláció TH1 Th2 functions Defence against extracellular pathogens bacteria, fungi, parasites Th2 cells stimulate the proliferation and differentiation of naive B cells Cytotoxic+ T-cells ! EFFEKTOR T LYMFOCYTES !! MHCI is present in all the nucleated cells Intracellular pathogens can be presented on all the cells Any cell is infected, can be killed by cytotoxic T cells MHCII present extracellular antigens to helper T cells. Helper T cells direct the immun eresponse by the pruduced cytokines. ! ! T helper cells (TH cells) assist other white blood cells in immunologic processes Cytotoxic T cells (TC cells, or CTLs) destroy intracellularly infected cells and tumor cells Fin Mi dönti el, hogy egy Th sejt milyen típusú ! Az antigénprezentáció mellett megjelenő citokin termelés meghatározza az immunválasz irányát Key step in Th1 differentiation is the production of IL-12 by Macrophages or DCs that will result in the INF-γ production by the T cells and NK cells. A key step in Th2 differentiation is the production of IL-4 by Mast cells and eosinophil granulocytes then later the T cells join to produce IL-4. A key step in Th2 differentiation is the production of IL-4 by Mast cells and eosinophil granulocytes then later the T cells join to produce IL-4. The three types of effector T cell produce distinct sets of effector molecules