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T cells T helper cells (TH cells) assist other white blood cells in immunologic processes Cytotoxic T cells (TC cells, or CTLs) destroy virally infected cells and tumor cells T cells •MHCI, presentation of intracellular pathogens •MHCII, presentation of extracellular pathogens •T cell receptor (TCR) •T cell activation •Cytotoxic T cells •Helper T cells 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 Dendritic cells take up antigen in the tissues, migrate to peripheral lymphoid organs, and present foreign antigens to naive T cells. Interaction of antigen presenting cell and T cell T cell T cell TCR MHC peptid Antigen presenting cell APC T cells •MHCI, presentation of intracellular pathogens •MHCII, presentation of extracellular pathogens •T cell receptor (TCR) •T cell activation •Cytotoxic T cells •Helper T cells System optimalization 1: How can the immune system monitor the intracellular enviroment? How can the immune system detect the intracellular pathogens? PRR Antigen presentation Display intracellular peptides on the surface of cells MHC Major histocompatibility complex cell surface molecules mediate interactions of T cells with antigen presenting cells MHCI Expressed by all nucleated cells the expression is regulated by cytokines or intectious agents. PEPTIDE 2 3 1 2m STRUCTURE OF CLASS I MHC MOLECULES A polymorphic α chain and and a non-polymorph β2 mikroglobulin α1 és α2 domains are responsible for peptide binding Cleft geometry -chain -chain Peptide 2-M MHC class I accommodate peptides of 8-10 amino acids Peptide -chain MHC class II accommodate peptides of >13 amino acids CYTOSOL-DERIVED PEPTIDES ARE PRESENTED BY MHC-I FOR T-CELLS Degradation of endogenous proteins takes place in the proteasomes, they are presented on cell surface by MHC I MHC do not recognize or distinguish self and nonself peptides ! Antigen presentation goes in the absence of pathogen or T cells as well MHCI Displays intracellular antigens to cytotoxic T cells RECOGNITION OF ENDOGENOUS ANTIGENES BY T-LYMPHOCYTES MHCI is expressed by all nucleated cells Tc TCR Peptide MHCI Endogenous Ag APC Peptides of endogenous proteins bind to class I MHC molecules presented to cytotoxic T cells T cells •MHCI, presentation of intracellular pathogens •MHCII, presentation of extracellular pathogens • antigen presenting cells •T cell receptor (TCR) •T cell activation •Cytotoxic T cells •Helper T cells System optimalization 2: MHCI present the intracellular area. Next step, how could the MHC molecules (and the T cells) monitor the extracellular enviroment? MHCII Expressed by professional antigen presenting cells Macrophage, dendritic cell, B cell STRUCTURE OF CLASS II MHC MOLECULES PEPTIDE 1 1 2 2 STRUCTURE OF CLASS II MHC MOLECULES A polymorphic α and a polymorphic β chain PEPTID 1 1 2 2 α1 and β1 domens are responsible for peptide binding PEPTIDE Cleft geometry -chain -chain Peptide 2-M MHC class I accommodate peptides of 8-10 amino acids Peptide -chain MHC class II accommodate peptides of >13 amino acids Presentation of extracellular peptides by MHCII !! MHCII Displays extracellular antigens to helper T cells MHC do not recognize or distinguish self and nonself peptides Antigen presentation goes in the absence of pathogen or T cells as well The two antigen presentation pathways function in a parallel simultaneous way A type of MHC molecule presents a lot of different peptides in the same time. Most likely only a few of them, if any, derived form pathogen. (one MHC molecule present only one peptide, millions of MHC present several thousand different peptides) Antigen presentation by MHCII: • Requires professional antigen presenting cells • Exogen antigens • Helper T cells • CD4+ cells RECOGNITION OF EXOGENOUS ANTIGENES BY HELPER TLYMPHOCYTES Th TCR Peptide MHCII Exogenous Ag Peptides of exogenous proteins (toxin, bacteria, allergen) bind to class II MHC molecules presented to helper T cells T cells •MHCI, presentation of intracellular pathogens •MHCII, presentation of extracellular pathogens • antigen presenting cells •T cell receptor (TCR) •T cell activation •Cytotoxic T cells •Helper T cells MHCII Expressed by professional antigen presenting cells Macrophage, dendritic cell, B cell PEPTIDE 1 1 2 2 Macrophage, DC MHCII PRR or opsonization Degradation of Patogen in the lysosome Peptide MHCII connection Exogen Ag APC Fagocytosis Constitutive checking of the extracellular enviroment (fagocytosis, pinocytosis) Summary of APCy Represent the extracellular enviroment Represent the intracellular enviroment 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 T cells •MHCI, presentation of intracellular pathogens •MHCII, presentation of extracellular pathogens •T cell receptor (TCR) • Structure • Comparision with BCR •T cell activation •Cytotoxic T cells •Helper T cells 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 s ss ss CH2ss ss CH3ss s s Membrane-bound heterodimer composed of an α chain and a β chain, each chain containing one variable (V) region and one constant (C) region Both the α chain and β chains of the TCR participate in specific recognition of MHC molecules and bound peptides CD3 CD3 T cells •MHCI, presentation of intracellular pathogens •MHCII, presentation of extracellular pathogens •T cell receptor (TCR) • Structure • Comparision with BCR •T cell activation •Cytotoxic T cells •Helper T cells TCRs only function as membrane receptors B cell TCR T cell Plasma cell TCR has a single antigen recognition unit 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 ACCESSORY CELL ANTIGEN BINDING NO INTERACTION V T-CELL ACTIVATION C Antigen receptor B-CELL / 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 B cell epitope T cell epitope recognized by B cells recognized by T cells proteins polysaccharides lipids DNA steroids etc. (many artificial molecules) proteins mainly (8-23 amino acids) cell or matrix associated or soluble requires processing by APC TCR-BCR similarity: Immunglobulin domain structure VDJ ---- numerous, randomly generated specificity One cell carries only one specificity Antigen presence--- initiates the clonal expansion of the cells that recognizes it Daughter cells have the same specificity (affinity maturation in B cells) as the progenitor Cells that recognizes self antigen are eliminated in the primary lymphatic tissues (bone marrow, thymus) But TCR do not recognize free antigen, only MHC peptide complex Recognizes only protein antigens No soluble form TCR has a single antigen recognition unit Other effector functions: BCR Neutralization Opsonization, increase phagocytosis complement activation NK-cell activation TCR Citotoxicity (Citokine production) T cells • MHCI, presentation of intracellular pathogens • MHCII, presentation of extracellular pathogens • T cell receptor (TCR) • T cell activation • Cytotoxic T cells • Helper T cells Macfarlane Burnet (1956 - 1960) CLON SELECTION HYPOTHESIS Antibodies are natural products that appear on the cell surface as receptors and selectively react with the antigen Lymphocyte receptors are variable and carry various antigen-recognizing receptors ‘Non-self’ antigens/pathogens encounter the existing lymphocyte pool (repertoire) Antigens select their matching receptors from the available lymphocyte pool, induce clonal proliferation of specific clones and these clones differentiate to antibody secreting plasma cells The clonally distributed antigen-recognizing receptors represent about ~107 – 109 distinct antigenic specificities Macfarlane Burnet (1956 - 1960) CLON SELECTION HYPOTHESIS Lymphocytes are monospecific cells Antigen engagement result in the activation of lymphocytes Activated lymphocytes differentiate and proliferate but keep their antigen specificity Lymphocytes reacting with self antigen during their development in the primary lymphoid organs, become inactivated or die by apoptosis. TCR can recognize only the MHC peptide komplex !! T cell response requires the DC-mediated antigen presentation in the secondary lymphoid organs Antigen recognition of T cells APC T Antigen recognition of T cells Protein degradation to peptide Peptide-MHC association Antigen presenting cell Peptide/MHC complex expression on the cell surface TCR recognizes the peptide/MHC complex T cell MHC RESTRICTION T-sejt T-sejt TCR TCR M HC MHC MHC APC APC APC T-sejt TCR One single T-cell receptor can recognize a given MHC – peptide complex The TCR-specific peptide is recognized only when its presented with an MHC on which the TCR had been selected during its development in the thymus If the peptide binds to another MHC molecule no T-cell recognition occurs (by this T cell) If the same MHC molecule binds another peptide, no T-cell recognition occurs Specificity of innate immunity Specificity of T cells Tc Distinct T cell receptors Peptides derived from different microbes peptid Tc MHC APC APC Specificity of innate immunity ( direct connetion between innate cells and pathogen ) Specificity of T cells Tc Distinct T cell receptors Peptides derived from different microbes peptid Tc No direct connetion between T cell and pathogen MHC APC APC APC-T cell connection Since there is no soluble TCR, effector funcions are mediated by the T cells itself: Citotoxicity Citokine production (review) Phases of T cell response T cell response The proliferation of T cells is restricted to the secondary lymphoid organs. Antigen is delivered to these organs by DCs Antigen recognition! Two steps of T cell activation: 1. Naive T cells recognize the antigen Activation, proliferation, differentiation to effector cells 2. Effector T cells recognize the antigen Activation, effector functions A naiv T-sejt válasz a hivatásos antigén prezentáló sejtek (általában az érett dendritikus sejtek) antigén prezentációját igényli DC-k Antigén felvétele DC-k Aktiválódása, érése DC vándorlása Érett DC-k Antigén prezentációja, a naiv T-sejteknek Two steps of T cell activation: 1. Naive T cells recognize the antigen Activation, proliferation, differentiation to effector cells • Professinal antigen presentibg cells (mostly DC) • In the secondary lymphatic organs 2. Effector T cells recognize the antigen Activation, effector functions • Any antigen presenting cells • anywhere T cells •MHCI, presentation of intracellular pathogens •MHCII, presentation of extracellular pathogens •T cell receptor (TCR) •T cell activation •Cytotoxic T cells •Helper T cells CITOTOXIC T LYMPHOCYTES cytotoxic T cells Infected or tumoric cells T lymphocytes recognize virus-infected cells virus Mechanisms of CTL-mediated killing of target cells Activated effector CD8+ T cells kill their target cells by apoptosis. CD8+ T cells induce apoptosis by two different pathways: - release of various cytotoxins (killing of infected or tumor cells) - activation of membrane-bound, cell-surface receptors containing death domains (e.g. Fas-FasL) (This mechanism is used mainly to regulate lymphocyte numbers.) KILLING OF TUMOR CELLS BY CTL Cytotoxic T lymphocytes recognize virus-infected or tumor cells T cells •MHCI, presentation of intracellular pathogens •MHCII, presentation of extracellular pathogens •T cell receptor (TCR) •T cell activation •Cytotoxic T cells •Helper T cells • Th1 • Th2 • Th17 • Follicular helper T cells Recognition of the presented antigen induces cytokine production of helper T cells EFFECTOR CD4+ HELPER T LYMPHOCYTES SECRETE DIFFERENT CYTOKINES Th1 Th0 IFNγ Th2 IL-4 Inflammatory cytokines Anti-inflammatory cytokines Intracellular pathogens Parasites T cells •MHCI, presentation of intracellular pathogens •MHCII, presentation of extracellular pathogens •T cell receptor (TCR) •T cell activation •Cytotoxic T cells •Helper T cells • Th1 • Th2 • Th17 • Follicular helper T cells •Helper T cells •Th1 principally against intracellular pathogens • enhance the killing of phagocyted microbes • NK cell activity • citotoxic T cell activity • Th2 principally against parasites and helminths • Increase the response to parasites by mast cells, basophil- and eosinophil granulocytes • Induce tissue regeneration •Helper T-sejtek •Th17 principally against extracellular pathogens • Inflammatory processes • Neutrophil activation • Mucosa associated immune response • Follicular helper T cells regulate the isotype switch (heterogen population) • Izotype switch • Function in the secondary lymphatic organs Most important cytocines: • Inflammatory cytokines: IL1, IL6, TNFα, IL12(NK cell activation) • Anti-viral cytokine: IFNα, IFNβ, INFγ • For cell activation: IL-2 T cell activation TH1 TH2 TH17 • β INFγ IL-4 IL-17 intracellular pathogens parasites extracellular pathogens 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 immune response by the pruduced cytokines.
