Immunology notes reg T and B cell activation

T cell activation

1. T CELL ACTIVATION AND IT’S TERMINATION

2. General features of T cell activation on recognition of peptide-MHC by TCR , T cell gets activated ,becomes proliferated, makes clonal expantion and differentiates into memory and effector T cells. T cells recognize antigens in lymphoid organs and ,in peripheral nonlymphoid tissues actively perform their effector functions. The activation of T cells requires recognition of antigens displayed on APCs, costimulators and cytokines produced by the APCs and by the T cells themselves. Naive T cells require activation by dendritic cells or other professional APC such as Macrophages or B cells.

3. Two signals are necessary for full T cell activation : • Signal 1 : generated by interaction of MHCpeptide with the TCR-CD3 complex • Signal 2 : generated by interaction of CD28 on the T cells and members of the B7 family on the APC, it is also called co-stimulatory signal J J

4. Important properties of the major accessory molecules

5. Naive T cells : They become activated on antigen recognition which is presented by APC (e.g. dendritic cells). Effector cells : cells which having short life with special functions such as cytokine secretion , helps B-cell and cytotoxic killing activity. Effector cells are derived from naïve or memory cells after antigen activation (e.g. CTLs) Memory cells : long-lived resting cells that are derived from naïve and effector cells. They respond faster and stronger to a subsequent challenge with the same antigen. Regulatory T cells : cells that can inhibit the proliferation of other T cell population which cause problem to host body . (e.g. CD4,CD25)

6. Interaction of T cells and APC Interaction between TCR and Ag/MHC alone is not strong enough to sustain the contact between T cells and APC Integrin and their receptors on T and APC strengthen the interaction so that TCR and CD28 receptors on T cells can receive prolonged and stable signals . Signals through integrin on T cells also enhance T cell activation. TCR-Ag/MHC

7. The role of costimulation in T cell activation

8. Role of costimulation and helper T cells in the differentiation of CD8 T cells

9. Superantigens induce T-cell activation by binding the TCR and MHC simultaneously Superantigens   (SAgs) are a class of antigens which cause non-specific activation of  T-cells resulting in polyclonal T cell activation and massive cytokine release. Superantigens ( viral or bacterial protein ) can be produced by  pathogenic microbes   as a defense mechanism against the immune system. Anti-CD3 and Anti-CD28 Antibodies   (CD28- SuperMAB) have also shown to be highly potent superantigens (and can activate up to 100% of T cells).

10. Formation of the immunological synapse This schematic diagram illustrates the steps in the formation of the immunological synapse. Before antigen recognition , various receptors on T cells and their ligands on APCs are dispersed in the plasma membranes of the two cells. When the T cell recognizes antigen presented by the antigen-presenting cell (APC), selected receptors on the T cell and their respective ligands are redistributed to a defined area of cell-cell contact, forming the synapse . The molecules in the central portion of the synapse form the central supramolecular activation cluster (cSMAC), and the molecules in the periphery form the peripheral supramolecular activation cluster (pSMAC) o

11. CD8+ T cells Naive CD8+ T cell differentiate into cytotoxic T cell lymphocytes (CTLs) which kill target APCs processing the correct MHC+ peptide. The mechanism involved are : Perforins : which makes the pores in membrane Granzymes : serine proteases that are capable of activating caspases. Fas-Fasl signalling resulting in apoptosis

12. Mechanisms of killing of infected cells by CD8 + CTLs

13. Different phases of T cell response

14. Activation of T cells generate effector and memory T cells

15. Activation of transcription factors in T cells.

16. Early tyrosin kinase signalling pathway Invariant components of TCR: the γ, δ and ε chains (Collectively known as CD3 complex ) and ζ chains . As TCR and MHC peptide binds , src family tyrosine kinases lck are activated. They phosphorylates specific motifs called I mmunoreceptor T yrosine based A ctivation M otif s ( ITAMs ) present on the ζ chain and CD3 subunits of TCR complex. Phosphorylation of these motifs promots recrutement and activation of zap-70 tyrosine kinase,which inturn activates several target adaptor proteins such as LAT and SLP-76. Phosphorylation of LAT and SLP-76 further activates phosholipase c – γ 1 ( plc- γ 1 ) enzyme by tyrosine phosphorylation. Plc- γ 1 catalyzes the formation of second messengers,inositol 1,4,5- trisphosphate ( IP3) and diacyle glycerol ( DAG) , which respectively triggers Ca2+ flux and contribute to protein kinase C ( PKC) and Ras activation. This ultimately activates several transcription factors such as NF-AT , NF- kB and AP1 which direct the transcription of new genes needed for Tcell response.

17. Function of IL-2 IL2 is autocrine T cell growth factor so it produced by T cell and helps them to proliferate

18. Major events involved in T-cell activation Event Example Cell-cell interaction T cell - APC CTL - target cell Receptor - ligand binding TCR - antigen/MHC Transmembrane signal transduction Activation of Lck and zap-70 Generation of second messengers 1,4,5-IP 3 and DAG Second-messenger effects Ca 2+ mobilization Protein kinase C activation Biochemical pathways Phosphatidylinositol pathway Ras pathway Cellular events Secretion of cytolytic granules Early gene activation c-Myc, c-Fos Intermediate gene activation Lymphokines, lymphokine receptors, nutrient receptors Late gene activation Genes involved in cell proliferation Il-2, IL-2R a , VLA-2 etc