Biology of T-cells, TCR, and antigen presentation Dr.Eman Albataineh, Associate Prof. Immunology College of Medicine, Mutah university • T cells involved in defense against intracellular and extracellular pathogens ( cell mediated immunity and help in humoral immunity) • Tumor immune response • allograft rejection • Regulation of Ab production αß T cells • About 90-95% of the blood T cells • The receptor has two polypeptide chains α and ß • Besides TCR is CD coreceptor – CD4+ = (Th) – or CD8+ = (Tc) αß TCR • Complete TCR is the αß receptor plus CD3 • Each chain constitute of one variable, one constant, hinge, transmembrane and cytoplasmic tail • Hypervariable regions on both Vα and Vß are the same as those of antibody located on Agbinding site and called CDR and they are 3 sites for each CD4 and CD8 • Cluster of differentiation (CD) are proteins expressed on T cells (CD4 or CD8), also they called co-receptors, have a role in binding the MHC and antigen and used to differentiate T cells by binding to monoclonal antibodies. CD8 T cells are Tc, CD4 T cell is Th1 or Th2 • Immunoglobulin superfamily also includes the antigen receptors of T and B cells, the co-receptors CD4, CD8, and the domains of MHC molecules. • Lymphocytes specific for a large number of antigens exist before exposure to the antigen, and when an antigen enters a secondary lymphoid organ, it binds to (selects) the antigenspecific cells and activates them. • This fundamental concept is called the clonal selection hypothesis. • The activation of naive T lymphocytes requires recognition of peptide-MHC complexes presented on antigen presenting cells (APC) Requirement for T cell activation • Specific ligand on the appropriate MHC molecule (signal1) • Co stimulatory molecules (signal 2) mainly CD28 • Signal 3, cytokine effect; T cells proliferation by the effect of IL-2 growth factor from DC to act on T cell, and from T cell to act on itself • If one of the first 2 is absent-----T cell anergy and tolerance • If both present-------T cell proliferation and differentiation to effecter and memory cells – Effecter cell in CD8 cells is always cytotoxic T lymphocyte (CTL). – Where as effecter CD4 T cells might be TH1 or TH2 cells. T cell costimulatory molecules for binding • Enough Naïve CD4&8 cell activation need binding of T cell with APC by: CD4/8 cell---APC 1- TCR/CD3---antigen +MHC (CD3 signal for TCR aggregation) 2-CD4/8---MHC2/1 And accessory or costimulatory molecules 1- CD28---B7 (CD80/86)(immunoglobulin super family, signal for costimulation and production of IL2 for T cell survival and proliferation,) 2- LFA-1---ICAM-1&2 3- CD40L---CD40 ( important for activation and isotype switch of B cells, increase expression of IL-12 by DC) 4- ICAM-3----DC-SIGN (specific to DC) costimulatory molecules on T cells Activated cells • Activated CD4+ helper T lymphocytes proliferate and differentiate into effector cells whose functions are mediated largely by secreted cytokines. For example; interleukin-2 (IL-2), which is a growth factor that stimulates the proliferation (clonal expansion) of the antigen-specific T cells. • Activated CD8+ lymphocytes proliferate and differentiate into CTLs that kill cells harboring microbes in the cytoplasm. These microbes may be viruses that infect many cell types or bacteria that are ingested by macrophages but escape from phagocytic vesicles into the cytoplasm (where they are inaccessible to the killing machinery of phagocytes, which is largely confined to vesicles). By destroying the infected cells, CTLs eliminate the reservoirs of infection APCs • Antigen-presenting cells are distributed in tissues, blood and in the lymph node • Dendritic cells, Macrophages and B cells • Mature dendritic cells are by far the most important activators of naive T cells and activated by wide range of antigens (viral. Bacterial and allergens) • B cell bind soluble intact antigen and present it to TH by MHC2 • Immature dentritic cells, exist at tissues and sites of infection, they express MHC1 & 2 and phagocytic receptor PRR, but low adhesion molecules. • Internalization occur as a result of binding the Ag with PRR or by macropinocytosis. • After engulfing the pathogen they become mature DC; migrate to peripheral L.N. – lose their phagocytic activity – and express more adhesion molecules, MHC and costimulatory molecules, – secret chemotactic factors to attract naïve T cells to the LN. • Surface immunoglobulin (IGM or IGD) allows B cells to bind and internalize specific soluble intact antigen very efficiently. The internalized antigen is processed in intracellular vesicles where it binds to MHC class II molecules. These vesicles are then transported to the cell surface where the MHC class II:antigen complex can be recognized by Th2 cells. Because of high specificity, it is perfect when Ag concentration is low. T cells costimulatory molecules functions – CD28, the earliest accessory molecules induce signaling after TCR CD4/8 binding to MHC and antigen it initiate T cell proliferation by expression of IL-2 cytokine and its receptor. CTLA-4 is expressed in stead when the antigen is cleared So that T cell is regulated – CD40L that bind CD40 on B cells that lead to B cells activation Inappropriate Ag or MHC • CD4 bind MHC2 and CD8 bind MHC1 • TCR bind both the Ag and part of MHC • Self Ag result in immature DC and macrophages (no costimulatory molecules)….T cell anergy. In appropriate T cell activation; T cell stimulation by Super antigens • Super antigens; are a class of antigens which cause non-specific activation of T-cells resulting in and massive cytokine release from macrophages • Causes; staphylococcal enterotoxins and streptococcal M protein, Others include EBV and HIV. • Pathology; Bind in-appropriately to the outer part of Vß domain of the TCR and to outer part of MHC 2 and cause activation of massive no. of T cells and huge amount of produced cytokines, as the frequency of T cells that have Ag specific Vß domain is higher than to have both Ag specific Vα and Vß TCR (10% : 0.01%) • Immunological effects; increase in IL1, TNF alpha and IL2 as a result of increased macrophage activation by T cells….fever, massive vascular leakage and shock.