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CELL-MEDIATED SPECIFIC IMMUNITY

CELL-MEDIATED SPECIFIC IMMUNITY. T CELLS: PLAY A CENTRAL REGULATORY AND EFFECTOR ROLE IN THE IMMUNE SYSTEM. Regulation: is mediated by cytokines and cell-to-cell contact B cells and immunoglobulin production T cell cytotoxicity natural killer cells (NK)

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CELL-MEDIATED SPECIFIC IMMUNITY

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  1. CELL-MEDIATED SPECIFIC IMMUNITY

  2. T CELLS: PLAY A CENTRAL REGULATORY AND EFFECTOR ROLE IN THE IMMUNE SYSTEM Regulation: is mediated by cytokines and cell-to-cell contact B cells and immunoglobulin production T cell cytotoxicity natural killer cells (NK) cell chemotaxis  Effector function: T cell mediated specific cytotoxicity

  3. DIFFERENTIATION OF T CELLS plays in thymus cell-to-cell contact with epithelial and dendritic cells humoral factors   thymic hormones: small peptides thymosine, thymopoetin immunomodulation

  4. THE MOST IMPORTANT EVENTS IN INTRATHYMIC DEVELOPMENT OF T CELLS T cells in thymus: proliferate and differentiate (functional cell-surface molecules) rearrange genetic information coding TcR express TcR heterodimers on the surface induction of self tolerance is generated

  5. DIFFERENTIATION OF T CELLS migration in to thymus is non-random (homing) humoral chemotactic factors (chemokines) specific surface interactions differentiation is characterized by: migration from subcapsular sinus into medulla proliferation morfological changes changes in surface molecules majority of thymocytes is dying by apoptosis due to differentiation failure

  6. MEMBRANE MOLECULES OF T CELLS receptors for antigen: heterodimers TcR, TcR pan T cells: expressed on all T cells (CD7, CD2, CD3) subpopulations: helper inducer T cells CD4+ suppressor cytotoxic T cells CD8+ other subsets: thymocytes (CD1)

  7. FUNCTION OF SURFACE MOLECULES: recognition (TcR) activation signals transmission (CD3) activation (HLA DR, IL-2R) accessory (CD4, CD8) costimulatory (CD28, CTLA-4) adhesion(CD2)

  8. SURFACE MOLECULES OF T CELLS: recognition of Ag TcR accessory molecules CD4 (CD8) CD3 adhesion molecules CD2 receptors for cytokines T cell ICAM1 CD69 g b IL-2R a CD28 activation molecules CD25 b costimulatory molecules a CTLA 4 HLA II.

  9. RECEPTORS FOR ANTIGEN ON T CELLS (TcR) are surface molecules responsible for specific recognition of antigen which is processed in APC and presented in association with self HLA I (II) molecules heterodimer, member of immunoglobuline family (domain) pre TcR is premature form of TcR found on thymocytes majority of mature T cells express  heterodimer minority of mature T cells express  heterodimer

  10. RECEPTORS FOR ANTIGEN ON T CELLS (TcR) variable TcR domain: unique amino acids composition in antigen-combining site weak chemical forces between binding site of TcR and antigenic peptide are formed

  11. RECEPTOR FOR ANTIGEN ON T CELLS (TcR) DNA TcR V a (g) b (d) V S S S S D D J J S S C C S S S S

  12. BASIC IMMUNOLOGICAL REPERTOIR OF TcR       enormous number of T cells with different TcRs       approx. 1x1016 different TcR specifities in theory       overloading of theoretical coding capacity of genom       genetic information for TcR is specifically organised into gene segments       genetic information for TcR is specifically processed (gene rearrangement)

  13. REARRANGEMENT OF TcR GENE SEGMENTS Vn V4 RAG -1,2 RAG -1,2 V3 9 9 23 12 7 7 V1 V2 J1 J2 J3 n = hundreds n = tens n = single C 5´ 3´ V1 V2 Vn D1 D2 Dn J1 Jn D1 D2 rearrangement D3 J1 Jn 3´ C 5´ V1 D3 J1 transcription splicing J2 Jn DNA mRNA N C translation VARIABILE CONSTANT TcR  chain

  14. BASIC REPERTOIR OF TcR IS INCREASED BY uncorrected joining of V (D) gene segments to  J genes random insertion of nucleotides in to D-J region (enzyme TdT) unsuccesful rearrangement induces apoptosis of thymocytes

  15. EXPRESSION OF TcR TcR are expressed on cell in association with  CD3 complex - TcR: small cytoplasmic part - CD3: trimolecular complex - noncovalently associated with TcR - transmission of activation signals in to cell - ITAM: Immunoreceptor Tyrosin-based Activation Motif phosphorylation of tyrosine (kinases) - CD4: lck kinase - costimulatory interactions: - CD28, CTLA-4  B7.1, B7.2 - critical level of activation signals is necessary to start T cell activation and clonal expansion

  16. TcR - CD 3 COMPLEX ON T CELLS TcR a b CD 3 COMPLEX S S V g S S d e S S S S S C S S S S S   S S S S I T A M I T A M ITAM:Immunoreceptor Tyrosin-based Activation Motif

  17. IMMUNE RECOGNITION ACTIVATION OF T CELL T cell T cell T cell clonal expansion effector functions anergy apoptosis no effect  Krejsek, 2004

  18. INTERACTIONS BETWEEN T CELL AND APC CELL Tcell APC adhesion interaction ICAM-1 clonal expansion LFA-1 accessory interaction LFA-3 endogenous antigen CD2 signal II processing: peptide+ HLA I costimulation CD28 B7 transcription factors CD4 lck signal I TcR HLA II PRESENTATION a b P  STAT g CD3 STAT d P e JAK processing : peptide+ HLA II cytokines exogenous antigen

  19. Tcells migration Bcells NK T CELLS RECOGNIZE ANTIGEN SPECIFICALLY IN „CONTEXT“ COSTIMULATORY INTERACTIONS „context“ („danger patterns“) -accessory interactions - cytokine microenvironment = IInd signal COGNITIVE INTERACTION: TcR, HLA-Ag, CD4 (CD8) = Ist signal + activation of T cells clonal expansion effector and regulatory functions

  20. INDUCTION OF SELF TOLERANCE Basic immunological repertoir of TcRs is generated: randomly in advance without presence of Ags in embryonal life in thymus  Basic immunological repertoir of TcRs includes clones with highprobability of self-recognition (autoreactive) of T cells. Autoreactive clones of T cells have to be eliminated by selection.

  21. SELECTION: POSITIVE SELECTION: T cell clones are tested for affinity (not recognition) of self HLA I, II molecules NO AFFINITY: SELECTION (DELETION) NEGATIVE SELECTION: T cell clones are tested for recognition of self molecules quantitative phenomena EFFECTIVE RECOGNITION: SELECTION (DELETION) Mature T cell: toleration of self recognition of non-self.

  22. TH2 presentation of microbial. Ag (LPS, CpG, lipoteichoic a.) dendritic c., macrophage, intensive, long term IL-12 presentation of environmental. Ag nonmicrobial origin (allergens) B-cells, weak, short term IL-4 TH1 TH0 INF IL-4 INHIBITION TH1 TH2 TH2 cytotoxic reactivity antibodies production, isotypic switching TH1 REGULATORY AND EFFECTOR SUBSETS OF T CELLS mature T cells (TH0) differentiate into functionally distinct subsets after antigen stimulation

  23. IL-4 TH1 IL-5 TH2 INF IL-6 IL-2 TNF G-CSF IL-10 TH3 (T reg.) TGF  TH SUBSETS - CYTOKINES PRODUCED

  24. PHYSIOLOGICAL IMMUNE RESPONSE DURING INFECTION IS REGULATED BY OPTIMAL BALANCE BETWEEN TH1 AND TH2 SUBSETS. protective immunity against particular agent could be either TH1 or TH2 driven there are subsequent waves of both TH1 and TH2 reactivities in the course of natural infections implication for vaccine development

  25. IMMUNOPATHOLOGY: predominant TH pattern could be delineated for particular immunopathological diseases (TH1multiple sclerosis,TH2  atopy) the immunopathology –driven inflammation is regulated by the mix of both subsets activities

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