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. Downloaded from: StudentConsult (on 18 July 2006 08:13 AM) © 2005 Elsevier 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 HLAautoantigens 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 The Fate of T-lymphocytes in the Thymus Downloaded from: StudentConsult (on 18 July 2006 11:18 AM) © 2005 Elsevier Thymic education of lymphocytes The significance of the AIRE (Autoimmune regulator) • Transcription factor, in the thymus leads to expression of many somatic proteins of various organs . • The expression of autoantigens on HLA-antigens leads to a negative selection of T-lymphocytes. • AIRE deficiency leads to development of various autoimmune diseases (endocrine glands, liver, stomach), autoantibodies agains IL-17lead to mucocutaneous candidiasis (so called APECED syndrome). https://step1.medbullets.com 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 Downloaded from: StudentConsult (on 18 July 2006 11:18 AM) © 2005 Elsevier V, D and J genes involved in T- and B- cell receptor formation Downloaded from: StudentConsult (on 20 July 2006 09:34 AM) © 2005 Elsevier 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. 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 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 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-lymphocytes are essential for stimulation of B-lymphocytes Th 17 cells • Important in protection against bacteria and fungi. • Differentiate after stimulation by IL-6, IL- 1b, also IL-23 plays very important role • Secretion of IL-17, IL-21, IL-22. • Pathology – involved in chronic imfammatory processes, 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 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 (i-Treg). • Mechanisms of regulation: Production of TGF b, expression of CTLA-4 …. TR-1 Lymphocytes • Antigen-induced regulatory CD4+ cells. • Develop from antigen stimulated Tlymhocytes in the environment of IL-10. • Tolerance of foreign antigens. • Very similar are „Th3 cells“. 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+