CELL-MEDIATED SPECIFIC IMMUNITY

PLAY A CENTRAL REGULATORY AND EFFECTOR ROLE IN THE IMMUNE SYSTEM 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

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

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

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  

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)  

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

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 CD28 a CD25 activation molecules b costimulatory molecules a CTLA 4 HLA II.

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  

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

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

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)  

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

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  

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

TcR - CD 3 COMPLEX ON T CELLS a b CD 3 COMPLEX S S V S S g 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

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

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

clonal expansion „context“ + = Ist signal = IInd signal activation of 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 Tcells Bcells migration NK effector and regulatory functions

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 high probability of self-recognition (autoreactive) of T cells.   Autoreactive clones of T cells have to be eliminated by selection.

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.

REGULATORY AND EFFECTOR SUBSETS OF T CELLS mature T cells (TH0) differentiate into functionally distinct subsets after antigen stimulation 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 TH0 INHIBITION INF IL-4 TH1 TH2 TH1 TH2 TH1 TH2 cytotoxic reactivity antibodies production, isotypic switching

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

protective immunity against particular agent 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

predominant TH pattern could be delineated for 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