T-Cell Mediated Immunity
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T cells are activated through the recognition of antigen peptides presented on MHC complexes on antigen presenting cells (APCs). This leads to T cell proliferation and differentiation into effector T cells. Cytotoxic T cells recognize endogenous antigens on MHC I to kill infected cells, while helper T cells recognize exogenous peptides on MHC II and secrete cytokines to stimulate macrophage activation or B cell antibody production. Full T cell activation requires both antigen recognition by the TCR and co-stimulatory signaling between molecules such as B7 and CD28.
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T-Cell Mediated Immunity
- 1. Lymphocytes Trafficking & T- Cell Response Dr Alok Tripathi Department of Biotechnology aquaimmuno@yahoo.co.in
- 2. T Cell-Mediated Immunity Headings • T Cell Activation • Properties of Effector T Cells • Cytotoxic T Cells • Macrophage Activation by Th1 (Inflammatory T) Cells This Presentation will help you see how T cells are activated by antigen presented on APC. understand the properties and functions of effector T cells.
- 3. Headlines in Nutshell Singling between APC & T cells depends upon CAMs CAMs allow them to come closure, so that Ag specific interaction can occur, if it would be! After this adhesion, MHC- peptide & TCR come closure to bind up This is further facilitated by LFA-1 for more strong binding Meanwhile, T cell, in complex, starts dividing & daughter cells remain attached to them & receive activation signal.
- 4. Self-MHC restriction of the T-cell receptor (TCR). A particular TCR is specific for both an antigenic peptide and a self-MHC molecule.
- 5. I. Importance of T lymphocytes Both T and B cells are needed to generate an Ab response Helper T cells activate B cells to produce Ab CTC are the other type of T cell, which actively kill other cells T cells are clonally selected via Ag recognition by the T cell receptor T cell Ag recognition is similar (e.g. TCR, Ig are homologous) to that in B cells, but distinct in mechanism T cells develop in the thymus (this is the principle function of this organ)
- 6. Effector Cells in Adaptive Immunity Effector T Cell Pathogen Location Antigen Presentation Target Cell Action Cellular Immunity Tc CD8 cytotoxic Cytoplasm Infected cell MHC I Infected cell apoptosis Th1 CD4 inflammatory Macrophage vesicles Macrophage MHC II Macrophage activation to kill pathogen Humoral Immunity Th2 CD4 helper Extracellular APC MHC II B cell antibody production
- 7. T Cell Activation Adaptive T cell-mediated immunity is driven by activation of T cells: cytotoxic T cells activated by endogenous antigen to kill infected cells, helper T cells activated by exogenous antigen to stimulate MΦ killing of endosomal pathogens. Adaptive humoral immunity also usually involves T cell activation to produce cytokines that stimulate B cell antibody synthesis.
- 8. T Cells Recognize Ag by a Unique Mechanism T cells recognize linear 9-10 aa peptide sequences T cells only recognize Ag’s presented on the surfaces of APC MHC restriction: the MHC allele expressed on the APC must be correct to stimulate T cells
- 9. Major Histocompatibility Complex (A) Discovery of the MHC discovered by mapping cell surface antigen responsible for tumor graft rejection the surface antigen is the MHC, recipient and donor must have matching MHC’s for graft to be accepted the MHC is called H-2 in mice and HLA in humans
- 10. Major Histocompatibility Complex The MHC locus encodes three classes of molecules MHC Class I Dimer of chain and 2m (not in locus) Three types, HLA A, B, C (in mouse, H-2K, -2D, -2L) Expressed on all cell surfaces except neurons and RBC Special subclass Ib is nonpolymorphic and tissue specific, related to bacterial pathogen response MHC Class II Heterodimer of and chains Three types DP, DQ, DR (in mouse I-A, I-E) Only expressed on APC’s MHC Class III related to complement and cytokines, irrelevant to this topic
- 11. MHC genes are highly polymorphic polymorphism in HLA genes for both class I and II is “balanced” nomenclature: HLA A*(allele #) (in mouse, superscript is allele type) most variation is localized to Ag binding domains (1 2 in class I, 1 1 in class II
- 12. MHC restriction is mediated by specific recognition by the TCR T cells are activated only if APC expresses the correct MHC Can test which MHC is responsible directly (correlate genotypes with response) or by specific blocking with antibodies Only one TCR needed to recognize both Ag and MHC
- 13. IV. The T Cell Receptor Discovered by clonotypic Ab and subtractive hybridization The TCR is made of two chains, , similar to Ig; each have one variable and one constant region TCR gene rearrangement rearranges by VJ, by VDJ using the RAG’s junctional diversity is important but hypermutation is not
- 14. How Ag is recognized APCs must process antigen before recognition occurs (hence, a time lag) MHC molecules bind a single, short Ag peptides of 9-10 aa (not TCR!) MHC molecules are specific in binding only certain peptides Complexity of immunogens and diversity of MHC expressed allows response to lots of pathogens, but susceptibility varies with MHC genotype The 1 and 2 domains of MHC form a catcher’s mitt with a groove to bind peptides; anchor positions give great specificity at those residues
- 15. Model for Ag Recognition by T Cells Uptake of Ag by APC Processing of Ag (proteolysis) Presentation of Ag peptide fragment on MHC Recognition of MHC-Ag complex by T cells (this is MHC restricted)
- 16. VII. T Cell Subsets Two classes of T cells 1) CD4+ Recognize exogenous Ag on MHC II on APC’s Release cytokines (IL2 T cell proliferation, IL4,5,6 B cell activation) Ag taken up by endocytosis, cleaved in lysosome For B cells, Ag binding to surface Ig results in rapid uptake of Ag Invariant chain (Ii) blocks MHC II binding site until fusion with lysosome 2) CD8+ Recognize endogenous (viral) Ag on MHC I on all cells (except neuron, RBC) Cause cytolysis of infected cell Viral proteins cleaved by protesome, enters ER through TAP1/2 transporters
- 17. VIII. T cell/APC interaction The CD’s interact specifically with their MHC; also coupled to signaling pathway (lck) Interactions between accessory proteins are required for T cell activation Superantigens (e.g. some bacterial endotoxins) promote T cell activation by binding TCR and MHC outside of cleft huge number of T cells activated eventually lead to toxic shock syndrome IX. Other Ag specific T cells can be detected with labeled MHC or MHC-Ig molecules HIV coat protein gp120 binds CD4, first step in virus infection
- 18. Key Adhesion Molecules in T-Cell Activation Ig Superfamily Adhesion Molecule Tissue Distribution Integrin Legend CD2 (LFA-2) T cells LFA-3 on APC ICAM-1 (CD 54) Activated endothelium dendritic cells T cells LFA-1 on T cells MAC-1 on macrophages ICAM-2 (CD102) Resting endothelium LFA-1 on T cells ICAM-3 (CD50) Naïve T cells DC-SIGN on dendritic cells LFA-3 (CD58) Lymphocytes APC CD2 on T cells
- 19. CD40 P → mIgM & mIgD APC Ÿ ← TCRs Ag MHC-II CD40L IL2,IL4, IL10, IL5, & IFN γ B7 & CD28
- 22. Naïve T Cell MHC-I~Peptide CD-8 T Cell MHC-II CD-4 T Cell Co-Stimulatory Signals APC Only professional APC (DC, NK & B- Cells ) have both MHC-I;II and can deliver co- stimulatory signal Proliferate & Differentiate Perform their function when they encounter Target cell- MHC~peptide
- 23. APC [B-Cell] Th Y Ag MHC-II P B7 CD-28 TCR CD-40 CD-40L CK CO-STIMULATORY SIGNALS Nucleus Singling Cascades
- 24. Lymphocytes Trafficking Definition: “Trafficking of lymphocytes between tissue, the blood stream and lymph nodes enable antigen sensitive cells at which response is occurring” Recognisation of vascular adressins on vascular endothelium in secondary lymphoid organ
- 25. Mechanism of T cell Activation
- 26. As the T-Cells Adhere to APC Movements of TCR towards the Peptide~MHC Starts They come closure to each other and bind Thus the complex so formed will be [T-CELLS-TCR- PEPTIDE~MHC-APC] • LFA-1 changes its confirmation Binding become tighter • This is required for the long time to Activate the cells After the receiving stimulation signal T cells starts dividing and its progeny still attached to the mother cells and received activation signals To activate the T cells APC has to delivered two signals • To TCR via MHC~Peptide Complex • Co-stimulatory signal via interaction of B7 to CD-28
- 27. In general the same cell must delivered the antigenic and co-stimulatory signal simultaneously for the activation of the T cell. • Not all self reactive T cells are deleted in the Thymus • Since some self antigens are appropriate in the other tissues This is because : Now if Ag & Co-stimulatory signal could be delivered separately, T cells could be stimulated by SELF PEPTIDE on Non APC & become fully activated to make an auto immune response by an APC presenting different peptide The T cells which binds to Ag and couldn’t get co stimulatory signal become ANERGIC and can't responds in future even if proper co stimulation is received Why these cells are inactivated without killed is not known !!!!!!!!!!! APC=DC,Mᶲ or B cells: DC deliver both signal and are the best APC and are the responsible for the activation of the most of the naïve cells
- 28. CD-40L T-Cells Ag & Co-Stimulatory Signals Activated T Cells Express Other receptors Enhance Co stimulation APC CD-40 To provide more co stimulation Express More B7 molecules To send activation signals to T cells Activate M & B- Cells Further Interaction of APC & T Cells
- 29. The immune response therefore depends upon PUSH of the antigen stimulation to activate T cells in to effectors cells and PULL of negative signal that curtail T cells response B7CTAL-4 ICOS 4-IBB/CD-137 4-1BBL To further activate T & APC LICOS Inducible co stimulator Binds 20 times more avidly then CD-28 send activation signals