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T-lymphocytes, ontogenesis, surface markers. Subpopulations of T-lymphocytes and their functions. T lymphocytes- ontogenesis • The undifferentiated stem cell in BM gives rise to the lymphoid precursor cell which matures into 3 types of lymphocytes: • T lymphocytes • B lymphocytes • Natural killer (NK) cell • Pro-thymocytes come to the thymus where • continue the maturation into T lymphocytes Maturation of B lymphocytes continue in BM Surface markers of T cells • CD (cluster of differentiation) proteins- molecules on the cells membrane, allow the identification of cells • TCR- receptor for antigen • MHC gp I or II class CD proteins • allow an identification of T-cell subsets • CD 3 = important in intracellular signaling to • • initiate an immune response; closely associated with TCR CD 4,8 = are expresed on subclasses of mature T cells; CD4 reacts with MHC gp II.class),CD8 reacts with MHC gp I. class on macrophages CD 28- receptor for costimulator molecules CD80 and 86 Maturation of T lymphocytes Consist of three types of processes: • Proliferation of immature cells • Expression of antigen receptors genes • Selection of lymphocytes that express useful antigen receptor (TCR) TCR • Antigen receptors are encoded by several gene • • • segments that recombine during lymphocyte maturation Heterodimer consisting of 2 nonidentical polypeptide chains linked together by disulfide bonds TCR heterodimer is noncovalently associated with the γ,δ,ε chains of the CD3 molecule COMPLEX TCR- CD3 makes contact with both the Ag and MHC gp Subpopulation of T cells • Subpopulations of T cells have been defined according to their particular function and their CD membrane markers • Cytotoxic T lymphocytes = Tc;CD8+ - recognize the foreign epitope in association with class I MHC molecules • Helper T-lymphocytes = Th; CD4+ - recognize the epitopes in association with class II MHC molecules Cytotoxic T lymphocytes (Tc;CD8+) • cause lysis of target cells; are active against • • • tumors, virus-infected cells, transplanted allogenetic tissue release TNF- depresses proteosynthesis recognize the foreign epitope in association with class I MHC molecules destroy their target cells by releasing perforin (create poresin the cell membrane and cytoplasm escapes) and granzymes (degrading essential macromolecules) Helper T-lymphocytes (Th; CD4+) • recognize the epitopes in association with class II MHC • help B cells to produce antibodies and help phagocytes to destroy ingested microbes • subsets of Th cells: Th1, Th2 cells Th1 cells secrete: • INF-γ (gamma interferon) : activates macrophages to become more effective at killing phagocytosed microbes, supresses the development of Th2 cells • IL- 2 : stimulates survival and proliferation of T cells, called T-cell growth factor • TNF (tumor necrosis factor)- stimulates the recruitment of neutrophils and monocytes to sites of infection, activates these cells to eradicate microbes • IL-3 : promotes expansion of immature marrow progenitors of all blood cells • GM-CSF : acts on progenitors in the bone marrow to increase production of neutrophils and monocytes Th1 based immune reaction • Th1 cells stimulate phagocytes to eliminate ingested microbes. • Interferon gamma is the main Th1 cytokine. Th2 cells secrete: • IL-4 : induces differentiation of Th2 cells from naive CD4+ precursors, stimulation of IgE production by B cells • IL-5 : activates mast cells • IL-6 : stimulates the synthesis of acute phase proteins by hepatocytes • IL-10 : inhibits activated macrophages, supresses Th1 production • IL-3, GM-CSF Th2 based immune reaction • Th 2 response provide help for B cells and are essential for antibodymediated immunity • Antibodies are needed to control extracellular pathogens • The Th2 - type cytokines include IL 4, 5, and 13. Regulatory T cells • Express CD4, CD25, FoxP3 • Regulate the activation or effector function of other T cells • Are necessary to maintain tolerance to self antigens The role of thymus. Positive and negative selection of T lymphocytes. The role of thymus • In the two thymic lobes, lymphocyte precursors from the bone-marrow become thymocytes, and subsequently mature into T cells • Once mature, T cells emigrate from the thymus and constitute the peripheral T cell repertoire responsible for directing many facets of the specific immune system Phases of thymocyte maturation • A rare population of hematopoietic progenitors enters the thymus from the blood, and expands by cell division to generate a large population of immature thymocytes • Immature thymocytes each make distinct T cell receptors by a process of gene rearrangement. • This process is error-prone, and some thymocytes fail to make functional T cell receptors, whereas other thymocytes make T cell receptors that are autoreactive Positive and negative selection • Immature thymocytes undergo a process of selection, based on the specificity of their T cell receptors. • This involves selection of T cells that are functional (positive selection), and elimination of T cells that are autoreactive (negative selection) Thymus – positive selection of T - cells 1. precursor T cells enter thymus from the blood 2. they are presented with self-antigens 3. 4. complexed with MHC molecules on the surface of cortical epithelial cells only those thymocytes which bind the MHC/antigen complex with adequate affinity will receive a vital "survival signal" the other thymocytes die (>95%) Thymus – negative selection of T - cells 1. thymocytes that survive positive selection migrate towards the boundary of the thymic cortex and thymic medulla 2. they are again presented with self-antigen in complex with MHC molecules on antigenpresenting cells 3. thymocytes that interact too strongly with the antigen receive an signal for apoptosis Humoral immune response • The binding of antigen cross-links Ig receptors of specific B cells and then activation signals are delivered inside the B cell; the necessary second signal is provided by a breakdown product of the complement protein C3 • This process results in clonal expansion of B cells and secretion of low levels of IgM Affinity maturation = affinity of antibodies for protein antigens increases with prolonged or repeated exposure to the antigens • B cells migrate into follicles and form germinal centers, proliferate rapidly • B cells that recognize the antigen with high affinity are selected to survive Phases of humoral immune responses Primary immune response • Occurs during the first antigen exposure • The amounts of antibody produced is smaller, class IgM 2 types of antigens: • T- dependent – help from T helper cells is required; protein antigens • T- independent – antibody production is induced directly, without the involvement of T helper cells; typical are polysaccharides, lipids Secondary immune response • Occurs during subsequent antigen exposure • Higher amount of antibodies is produced • secondary responses show increased isotype switching (IgG, IgA, IgE) and affinity maturation (= production of antibodies with increased affinity to antigen) • Gives arise memory cells involvement Physiological mechanisms of regulation of the immune system. Immune mechanisms of regulation Immune system is regulated by: • Antigen • Antagonistic peptid • Antibodies • Cytokines and intercellular contact • T lymphocytes • Neuroendocrine regulation REGULATION BY ANTIGEN • Antigen competition – peptides from different antigens compete for binding-sites on the MHC gp = antigen is able to suppress expression of other antigen IMPORTANT IS : • the binding strenght of peptide to MHC gp II • density of peptid-MHC gp II complex on the surface of APC Immune response finishes after extinction of antigen – due to a short life-span of effector lymphocytes ANTAGONISTIC PEPTIDES • Agonists - peptide fragments of antigen with • • adequate binding to MHC gp, recognition by T cells with sufficient affinity – induce full response of T cells Partial agonists – induce a qualitative different response of T cells - peptides have a similar structure, bind adequately to MHC gp, but make too weak or too strong interaction with T cells Antagonists – induce anergy of T cells REGULATION MEDIATED BY ANTIBODIES • Antibodies have an effector and regulatory functions • Secreted antibodies – compete with BCR for antigen = negative regulators of B cells stimulation • Immune complexes of antibody and antigen – bind to the surface of B cells – inhibit B cells activation REGULATION MEDIATED BY CYTOKINES AND INTERCELLULAR CONTACT • Inhibition of cytokine effect by endocytosis of • • their receptors or by binding of inhibitors to their receptors Inhibitory receptors – protection against too easy T cells activation Apoptotic receptor (Fas) mediates a negative regulation after binding to ligand FasL on activated T cells – causes – lysis of cell NEGATIVE REGULATION mediated by T lymphocytes • Th2 cells produce IL-4, IL-10- suppress immune • • response of Th1 cells CD8+ T cells – secrete soluble forms of TCR compete with TCR on the surface of other cellsinhibition Regulatory Tr1 cells (CD4+)- secrete IL-10-antiinflammatory effect, induce tolerance to autoantigens NEUROENDOCRINE REGULATION • Neurotrasmiters influence leukocytes by • • • • binding to the specific receptors (noradrenalin) CS, growth hormons, thyroxin, endorfins – influence the leukocytes by binding to the specific receptors Leukocytes produce endorfins, TSH, growth hormon, vitamin D3, ACTH Cytokines influence nerve system (IL-1, IL-6) Stress influences immune systemcortocosteroids-activity of phagocytes, NK cells OTHER FACTORS • The same antigen can induce active immune • • • • response or active tolerance – depends on: Condition of immune system Character of antigen (size, structure of molecule) Dose of antigen (too low or too high dosesinduce tolerance) Route of antigen administration (s.c.-induce immune response, p.o. or i.v.- induce tolerance) Cytokines (overview, disposal according their function) Cytokines • Humoral factors - provide intercellular • • • • communication between immune cells + communication between immune system and other body systems Proteins secreted by leukocytes (and by other cells of immune system) Influence different cells of immune system through specific receptors Forms- secreted or membrane Effects - pleiotropic (1 cytokine has a several fysiological effects) Function of cytokines • Activating signals for cells – activate, regulate • • • • cell cycle, mitotic activity Cause changes of the cell membranes – increase of cytokine receptors expression Participate in reparation of tissues in the terminal phase of inflammation Regulate immune cells proliferation and differentiation in the immune organs Influence migration of the immune cells Classification of cytokines • Pro-inflammatory • Anti-inflammatory • With growth activity factor • Participating in humoral response IS • Participating in cell response IS • With antiviral effect Proinflammatory cytokines • IL-1 – produced by macrophages and T cells; • • • activates neutrophils, endothelial cells and T cells, induces synthesis of acute phase proteins in liver, causes fever IL-6 – produced by T and B cells, monocytes; regulates B cell differentiation and proliferation, synthesis antibodies; stimulates hepatocytes to produce acute phase proteins IL-8 – produced by monocytes, macrophages, endothelial cells; chemotactic factor for neutrophils TNF TNF • TNF α – produced by macrophages (+T a B cells, NK cells, neutrophiles,..) – participates on early phase of inflammation, induces expression of adhesive molecules on endothelial cells and leukocytes; stimulates proinflammatory protein production • TNF β- produced by T and B cells; similar effects Anti-inflammatory cytokines • IL-10 – produced by Th2 cells, monocytes, • • • macrophages, activated B cells; inhibits cytokine Th1, Tc and NK cells production; inhibits synthesis of pro-inflammatory cytokines by macrophages TGF-β – growth activator but also inhibitor of different cell types Regulates damaged tissues reparation by stimulation of intercellular substances synthesis; can inhibite T and B cell proliferation IL-4 CYTOKINES with activity of growth factors • SCF- stimulates stem cell proliferation, their • • • • release to the peripheral blood IL-3 – influences maturation of all cell lines IL-7 – growth factor of T cells IL-11 – growth factor of megakaryocytes IL-15 – induces proliferation of mast cells, Th and Tc cells CYTOKINES with activity of growth factors • G-CSF, M-CSF, GM-CSF – stimulate granulocytes and/or monocytes/macrophages proliferation and differentiation, prolongate their survival and increase their functional capacity during inflammation • EPO = erythropoetin- stimulates red cells differentiation CYTOKINE participating in humoral response of IS • IL-4 – produced by Th2 cells, mast cells and • • basophils; stimulates B and T cells proliferation, activates macrophages; growth factor of mast cells (anti-inflammatory effect) IL-13 – see IL-4 + chemotactic factor for monocytes and macrophages IL-5 – produced by Th2 cells, lymphocytes and mast cells; activates and stimulates B cells and eosinophils proliferation, stimulates Tc cells CYTOKINES participating in cell mediated response • IL-2 – produced by Th cells after stimulation by • • antigen, autocrine effect to Th cells; activating signal for Tc cells and NK cells; 2. signal for activation and differentiation of B cells IL-12 – produced by monocytes, macrophages; stimulates maturation Th0 into Th1 cells; activates NK cells; stimulates INF- γ production by Th1 cells; inhibites IgE secretion IFN-γ, GM-CSF CYTOKINE with antiviral effect • Interferons- anti-inflammatory, anti• • • prolifferative IFN-α, IFN-β - produced by cells with nucleus after stimulation by viruses Induce decomposition of viral nucleus acids and influence into translation of viral proteins IFN- α - in recombinant form – therapy of chronic active hepatitis B, hepatitis C Regulation of local concentration of cytokines • Biological effects are neutralized by binding to nature inhibitors and soluble forms of receptors for cytokines • MMP (matrix metaloproteases) release cytokines from molecules of intercellular substance • Elastases release binded cytokines External regulation of immune response • Substitutive therapy – immunoglobulins, C1-inhibitor • Non-specific immunostimulation : Isoprinosine, bacterial lysates, cytokines • Ag- specific immunotherapy: active immunisation – prophylaxis pasive immunisation – prophylaxis, therapy Therapy- Non-specific immunosupresion • corticosteroids • anti- inflamatory drugs (antihistaminics, inhibitors of pro- • • • inflamatory cytokines-monoclonal Ab agains TNF, nonsteroid anti-inflamatory drugs- metabolites of arachid acid) drugs affecting the proliferation of both T cells and B cells (Cyclophosphamide, Methotrexate, Azathioprine, Mycophenolate mofetil) drugs blocking the activation of lymphocytes (Tacrolimus, Sirolimus, Cyclosporin A) monoclonal antibodies – against IL-2 receptor