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T lymphocytes- ontogenesis

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

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T lymphocytes- ontogenesis

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  1. T-lymphocytes, ontogenesis, surface markers. Subpopulations of T-lymphocytes and their functions.

  2. 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

  3. 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

  4. 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

  5. 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)

  6. 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

  7. 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

  8. 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)

  9. 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

  10. 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

  11. Th1 based immune reaction • Th1 cells stimulate phagocytes to eliminate ingested microbes. • Interferon gamma is the main Th1 cytokine.

  12. 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

  13. Th2 based immune reaction • Th 2 response provide help for B cells and are essential for antibody-mediated immunity • Antibodies are needed to control extracellular pathogens • The Th2 - type cytokines include IL 4, 5, and 13.

  14. 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

  15. The role of thymus. Positive and negative selection of Tlymphocytes.

  16. 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

  17. 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

  18. 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)

  19. Thymus – positive selection of T - cells • precursor T cells enter thymus from the blood • they are presented with self-antigens 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%)

  20. Thymus – negative selection of T - cells • thymocytes that survive positive selection migrate towards the boundary of the thymic cortex and thymic medulla • they are again presented with self-antigen in complex with MHC molecules on antigen-presenting cells • thymocytes that interact too strongly with the antigen receive an signal for apoptosis

  21. 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

  22. 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

  23. Phases of humoral immune responses

  24. 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

  25. 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

  26. Physiological mechanisms of regulation of the immune system.

  27. Immune mechanisms of regulation Immune system is regulated by: • Antigen • Antagonistic peptid • Antibodies • Cytokines and intercellular contact • T lymphocytes • Neuroendocrine regulation

  28. 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

  29. 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

  30. 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

  31. 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

  32. 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 cells- inhibition • Regulatory Tr1 cells (CD4+)- secrete IL-10-anti-inflammatory effect, induce tolerance to autoantigens

  33. 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 system- cortocosteroids-activity of phagocytes, NK cells

  34. 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 doses-induce tolerance) • Route of antigen administration (s.c.-induce immune response, p.o. or i.v.- induce tolerance)

  35. Cytokines (overview, disposal according their function)

  36. 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)

  37. 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

  38. Classification of cytokines • Pro-inflammatory • Anti-inflammatory • With growth activity factor • Participating in humoral response IS • Participating in cell response IS • With antiviral effect

  39. 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

  40. 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

  41. 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

  42. 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

  43. 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

  44. 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

  45. 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

  46. 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

  47. 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

  48. 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

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