T-Lymphocytes Function, Development, Subpopulations Activation of T-lymphocytes •T-lymphocytes can be stimulated only by complexes of antigen-HLA antigen. •The HLA antigen must be the same as HLA antigens of the person from whom the lymphocytes originate= phenomenon of HLA restriction. S0241X-003-f001 Downloaded from: StudentConsult (on 18 July 2006 08:13 AM) © 2005 Elsevier top_logo Interaction TCR-polypeptide-HLA molecule Thymic education •Positive selection: survival of cells reacting with low affinity with HLA antigens expressed on antigen-presenting cells in the thymus. Only those cells that recognize HLA antigen of the concrete person survive. The non-reacting cells die by neglect. •Negative selection – those thymocytes that react with high affinity with complexes of HLA-autoantigens in thymus die by apoptosis. •It is supposed that more than 90-95% of thymocytes die during these processes. Development of lymphocytes in the thymus vývoj v Thymu 4A - Thym_Selection_nri1085-f1 The Fate of T-lymphocytes in the Thymus S0241X-004-f013 Downloaded from: StudentConsult (on 18 July 2006 11:18 AM) © 2005 Elsevier Thymic education of lymphocytes Strength of interaction between TCR and HLA-(antigen) complexes determines the fate of thymocytes Neglected cells Positive selectoion Negative selection Stength of interaction Cell death S0241X-004-f011 Downloaded from: StudentConsult (on 18 July 2006 11:18 AM) © 2005 Elsevier top_logo V, D and J genes involved in T- and B- cell receptor formation S0241X-005-f002 Downloaded from: StudentConsult (on 20 July 2006 09:34 AM) © 2005 Elsevier top_logo Activation and differentiation of T-lymphocytes Central role of T-lymphocytes in specific immune response Antigen-presenting cell Antigen Th cell B cell Tc cell Granulocyte Macrophage NK NK cell Determination of lymphocytes using cell surface antigens •CD (Cluster of Determination) antigens – antigens expressed on surface of leukocytes. •More than 400 such markers has been determined. •CD3+ – all T-lymphocytes. •CD3 +CD4 + – helper and majority of regulatory T-cells. •CD3 +CD8 + – predominantly cytotoxic T-cells. •Classical CD antigens cannot be used do determine Th1, Th2, Th 17 lymphocyte subsets – cytokine production must be used (usually intracytoplasmatic determination of cytokines). •CD19 + - B-lymphocytes. •CD16 +/CD56 +(CD3-) - NK cells. •Flow cytometry is used for CD markers determination. Surface stuctures on T-lymphocytes •T-cell receptor (TCR): –Variable chains a/b or g/d –Includes CD3 molecule – this part is responsible for signal transduction. •Co-receptors CD4 and CD8 - binding to HLA I or HLA II molecules •For T-cells activation co-stimulatory molecules are essential( the most important is CD28) – also signal transduction •Adhesion molecules (e.g. LFA-1) – enables physical contact between T-cells and antigen presenting cells. • S0241X-005-f003a Downloaded from: StudentConsult (on 20 July 2006 09:34 AM) © 2005 Elsevier Surface structures of T-lymphocytes Subpopulations of T-lymphocytes •Cytotoxic T-lymphocytes (CD8+): kill target cells. Activated by complex HLA-I –antigenic peptide. •Helper T-lymphocytes (CD4+): enable activation of macrophages (Th1) or B-cells (Th2) cells. They are activated by complexes HLA-II- antigenic peptide. •Regulatory T-cells (CD4+): important in the maintenance of immune tolerance. Subpopulations of Th-lymphocytes •Th1 lymphocytes –Produce IFN-g, IL-2, IL-3, –Stimulation of macrophages, pro inflammatory effect –Probably pathogenic in multiple sclerosis… •Th2 lymphocytes –Produce IL-3, IL-4, IL-5, IL-6, IL-10, IL-13 –Stimulation of antibody production, including IgE –Included in pathogenesis of allergic diseases •Th17 lymphocytes –Produce IL-17 –Important in chronic inflammation – –Also Th9, Th22lymphocytes – – Funkce T-lymfocytů Functions of T-lymphocytes Development of Th1 and Th2 cells Bacteria TH 1 TH 0 TH 2 Macrophage NK cell Mast cell Function of TH1 and Th2 cells Mast cell Macrophage Inhibits production Th1 cell Th2 cell B cell Eosinophil Cytokine environment decides the future development of Th0 cells Th1 lymphocytes •Secretion of IFN-g, IL-2, IL-3. •Differentiate after stimulation by IL-12, IL-18, IFN-g •Pro-inflammatory effect, stimulate function of macrophages. •Involved in pathogenesis of multiple sclerosis… •Down-regulation of Th2 cells by production of IFN-g •Involved in accute graft rejection Th1 bb aktivují Ma Function of Th1 cells Th2 lymphocytes • –Secrete IL-3, IL-4, IL-5, IL-6, IL-10, IL-13 –Differentiate after stimulation by IL-4 –Stimulation of antibody production, including IgE –Important in protection against parazites –Included in pathogenesis of allergic diseases –By production of IL-10 suppress function of Th1 cells. –Th2 predominance in pregnancy. • Th2 bb ativují B-lymfocyty Th2-lymphocytes are essential for stimulation of B-lymphocytes Th 17 cells •Important in protection against bacteria and fungi. •Differentiate after stimulation by IL-6, TGF-b, also IL-23 plays very important role •Secretion of IL-17, IL-21, IL-22. •Pathology – involved in chronic imfammatory states, including rheumatoid artritis, Crohn disease. • Cytotoxic T-lymfocytes •CD8+ •Foreign antigens are recognized in complex with HLA-I class antigens. •Mechanism of cytotoxicity: perforin (induction of membrane pores), various mechanism inducing apopsosis of the target cell (granzymes, FasL, lymfotoxin). •Produce various cytokines (Tc1 and Tc2 cells) • • Cytotoxic effect of CD8+ cells CD8 ly indukují apoptózu CD8 lymphocytes induce apoptosis of target cells IL-10 Types of regulatory T-lymphocytes Periphery From: Nature Immunology Treg lymphocytes •Thymic development •Express CD4+CD25+ •Involved in tolerace of autoantigens •Comprise approximately 5-10% of peripheral CD4+ lymphocytes •Can be incuced also in periphery by foreign antigens. • TR-1 Lymphocytes •Antigen-induced regulatory CD4+ cells. •Develop from antigen stimulated T-lymhocytes in the environment of IL-10. •Tolerance of foreign antigens. •Very similar are „Th3 cells“. Shody TCR a BCR T- and B-cells antigen-speciphic receptors gd-T-lymphocytes •Comprise approximately 5% of peripheral lymphocytes. •CD3+, CD4-CD8- •Low antigenic specificity. •Thymus in not necessary for their development. •Other than HLA antigens may be involved in antigen presentation. •Increased in mycobacterial infections, Erlichiosis, listeriosis. Intraepitelial T-lymphocytes •TCR of ab or gd type •Low antigenic specificity •Extrathymic differentiation •The first line of the specific immune response •Usually CD8+