Cellular Immunity PDF

CELLULAR IMMUNITY  CELL SURFACE RECEPTORS OF T CELL ◦ The TCR complex is a combination of the antigen recognition structure (TCR) and cell-activation machinery (CD3), that TCR determines the antigenic specific response of the T cell ◦ Each TCR molecule is made of of two different pol...

CELLULAR IMMUNITY  CELL SURFACE RECEPTORS OF T CELL ◦ The TCR complex is a combination of the antigen recognition structure (TCR) and cell-activation machinery (CD3), that TCR determines the antigenic specific response of the T cell ◦ Each TCR molecule is made of of two different polypeptide chains, like antibody each TCR chain has a constant region and a variable region ◦ The repertoire of TCR is very large and can identify a tremendous number of antigenic specificities (estimated to be able to recognize 1015 separate epitopes) TCR  CELL SURFACE RECEPTORS OF T CELL ◦ Each T cell clone expresses a unique TCR ◦ The CD3 complex is found on all T cells and consists of the ϒ-, δ-, ε-, and ξ- polypeptide chains ◦ The CD3 complex is the signal transduction unit for the TCR ◦ The activation of specific transcription factors in the nucleus by the CD3 complex, result to the activation of the T cell, and production of IL-12 , IL-2 and its receptor, IL-2R T CELL ACTIVATION TH CELL ACTIVATION CD4/CD8 T CELL ACTIVATION  CELL SURFACE RECEPTORS OF T CELL ◦ The CD4 and CD8 proteins are co-receptors for the TCR because they facilitate the interaction of the TCR with the antigen- presenting MHC molecule and can enhance the activation response ◦ CD4 binds to class II MHC molecules on the surfac of APCs ◦ CD8 binds to class I MHC molecules on the surfac of APCs and target cells ◦ CD4 or CD8 is found on α/β T cells but not on ϒ/δ T cells  CELL SURFACE RECEPTORS OF T CELL ◦ Accessory molecules express on the T cell include several protein receptors on the cell surface that interact with proteins on APCs and target cells; activation of the T cell, promotion of tighter interactions between the cells, or facilitation of the killing target cell ◦ These accessory molecules are as follows: 1. CD45RA (native T cells) or CD45RO (memory T cells) 2. CD28 or cytotoxic T-cell-associated protein 4 (CTLA-4) 3. CD154 (CD40L) 4. FasL CELL SURFACE RECEPTORS OF T CELL Antigen specific Cytokine-mediated Adhesion Co-stimulation stimulation signalling  CELL SURFACE RECEPTORS OF T CELL ◦ Adhesion molecules tighten the interaction of the T cell with the APC or target cell and may also promote activation ◦ Adhesion molecules include leukocyte function-associated antigen-1 (LFA-1), which interacts with the intercellular adhesion molecules (ICAM-1, ICAM-2, and ICAM-3) on the target cell ◦ T cell express receptors for many cytokines that activate and regulate T cell function ADHESION MOLECULES INITIATION OF T CELL RESPONSES Helper T-cell subsets  ANTIGEN PRESENTATION TO T CELL ◦ Activation of naİve T cell responses is initiated by DCs and then expanded by other APCs ◦ CD4 helper T cell are activated by the interaction of the TCR with antigenic peptide presented by class II MHC molecules on the APCs ◦ Co-stimulatory signal mediated by binding on the APC to CD28 molecules on the T cell is is required to induce growth of the T cell Co-stimulator signal Stimulation, Proliferation NoStimulation, B cells and T cells each need two signals  ANTIGEN PRESENTATION TO T CELL ◦ Partial activation (TCR interaction with MHC peptide) without co-stimulation leads to anergy (unresponsiveness) or apoptotic death (cell suicide) of the T cell ◦ This a mechanism for: 1. Eliminating self-reactive T cell in the thymus 2. Promoting the development of tolerance to self-proteins 3. Binding of the CTLA-4, instead of CD28, on T cell with B7 on target cell or APC cells can result in anergy toward the antigen  ANTIGEN PRESENTATION TO T CELL ◦ Once activated, the CD4 T cells exit the T cell sites of the lymph node and enter the blood or move to B cell zones of the lymph nodes and spleen ◦ Antigen presentation initiates close interactions between the T cell and APC that allow the CD40L and CD28 molecules on the T cell to bind CD40 and B7 molecules on the APC ◦ This interaction and the cytokines produced by the T cell will determine the function of the macrophages and DC and B cell will produce Ig Presentation of extracellular and cytosolic antigens to different subsets of T cells  CD4 T-HELPER CELL FUNCTION ◦ The different types of TH cells are defined by the cytokines they secrete and thus the responses that they induce ◦ Activation of TH1 response requires IL-12 ◦ TH1 cells are characterized by secretion of IL-2, IFN-ϒ, and TNF-β ◦ Activated TH1 cells also express the Fas ligand, which can interact with the Fas protein on target cells to promote apoptosis (killing) of the taget cell  THE TH1 RESPONSE ◦ The TH1 response usually occurs early in response to an infection and activates both cellular and antibody responses ◦ The TH1 responses amplify, local inflammatory reactions and DTH reactions by activating macrophages, NK cells, and CD8 cytotoxic T cells and ◦ Also expand the immune response by stimulating growth of B and T cells with IL-12  THE TH1 RESPONSE ◦ The inflammatory responses and antibody stimulated by TH1 responses are important for, eliminating intracellular infections and fungi but are also associated with cell-mediated autoimmune inflammatory diseases (eg,multiple sclerosis, Crohn disease) Subsets of T cells T cells Subsets Activation  THE TH2 RESPONSE ◦ The TH2 response occurs later in response to infection and acts systemically through antibody-mediated responses ◦ The TH2 response occurs in the absence of an IL- 12/IFN-ϒ signal from innate responses, and then IL-4 reinforces the continuation of TH2 responses ◦ TH2 cells release IL-4, IL-5, IL-6, and IL-10 cytokines that promote humoral ( systemic ) responses  THE TH2 RESPONSE ◦ These cytokines stimulate the B cell to undergo recombination events within the Ig gene to switch from production of IgM and IgD to production of specific subtypes of IgG, IgE, or IgA ◦ TH2 responses are associated with production of IgE, which is useful for antiheminth responses but mediates allergies ◦ TH2 responses can exacerbate an intracellular infection (eg, Mycobacterium leprae, Leishmania) by prematurely shutting off protective TH1 responses TH2 profile TH1 / TH2 Balance TH1 / TH2 TH1 cytokines stimulate their production and downregulate TH2 differentiation. The reverse is true for the TH2 cytokines.  THE TH17 RESPONSE ◦ Initial antibacterial and antifungal responses are mediated by the TH17 cells ◦ TH17 cells make cytokines, such as IL-17, IL-22, IL-6 and TNF-α and proinflammatory chemokines ◦ TH17 responses would also provide protection in immunoprivileged sites, such as the eye, where there is an abondance of TGF-β ◦ TH17 responses are associated with cell-mediated autoimmune inflammatory diseases, such as rheumatoid arthritis TH17  THE TH17 RESPONSE ◦ CD4+ TH cells are named because they release high amounts of IL-17 which has wide range of effects by acting on numerous cell types. ◦ Th17 effector cells are induced in parallel to Th1, and, like Th1, polarized Th17 cells have the capacity to cause inflammation and autoimmune disease.  TH TREG CELLS RESPONSE ◦ The Treg cells expressing CD4 CD25 are antigen specific suppressor cells ◦ These cells prevent the development of autoimmune responses by producing TGF-β and IL-10 help to keep T cell responses under control, and promote memory cell development Treg  TH FOLLICULAR CELLS RESPONSE ◦ T follicular helper cells (Tfh) are a specialized subset of CD4+ T cells that were first identified in the human tonsil. ◦ They play a critical role in protective immunity helping B cells produce antibody against foreign pathogens. Tfh are located in the tonsil, spleen and lymph nodes. ◦ Uniquely, Tfh are found in the B cell zone and in close interactions with B cells. ◦ Tfh can also be identified in the circulation.  TH FOLLICULAR CELLS FUNCTION ◦ Tfh directly providing co-stimulation to the B cells via the co- stimulatory molecule CD40 interacting with CD40-ligand (CD40-L) on the B cell and by producing IL-21 which drives B cell proliferation. ◦ Circulating Tfh numbers have been shown to increase in number in the blood of patients with autoimmune diseases, including systemic lupus erythematosus and rheumatoid arthritis. TH FOLLICULAR CELLS  THE TH9 RESPONSE ◦ TH cells new subset is Th9 cells, played an important role in various immune-related diseases, including tumors, inflammatory diseases, parasite infection, and other diseases. ◦ CD4+T cells induced by transforming growth factor β (TGF-β) and IL-4 and secretes IL-9 named as Th9 cells. ◦ Th9 cells have been demonstrated to facilitate antitumor responses. Th9 cells participate in the lesion of many diseases besides tumor, such as allergic inflammation, and parasitosis. B cell Regulation  CD4 8 T-CYTOTOXIC CELL FUNCTION ◦ CD8 T cells include cytotoxic T lymphocytes (CTLs) and suppressor cells ◦ CTLs are part of the TH1 response and are important for eliminating virally infected cells and tumor cells ◦ CTL response is initiated when CD8 T cells in the lymph node are activated by antigen-presenting DCs and cytokines produced by TH1 CD4 T cells, including IL-12 ◦ Presentation of the antigen on MHC I may be the result of a virus infection or tumor by a DC  CD8 T-CYTOTOXIC CELL FUNCTION ◦ The activated CD8 T cells divide and differentiate into mature CTLs ◦ When the activated CTL find a target cell, it binds ◦ Granules containing toxic molecules, granzymes and a perforin move to the sites of interaction and release their contents into the pocket (immun synapse) ◦ Perforin generates holes in the target cell membrane to allow the granule contents to enter and induce apoptosis (programmed cell death) in the target cell Both types of cytotoxicities (antibody dependent and independent) involves the release of cytoplasmic granules containign perforin and granzymes. Perforin is a monomeric pore-forming molecule that is homologoue both in function and structure to C9 complement cascade membrane.  NKT CELL FUNCTION ◦ NKT cells are like a hybrid between NK cells and T cells They express an NK cell marker, and an α/β TCR ◦ Unlike other T cells , the TCR repertoire is very limited ◦ They may express CD4, but most lack CD4 and CD8 molcules (CD4- CD8-) ◦ NKT cells are release large amounts of IL-4 and IFN-ϒ ◦ NKT cells help in the initial response to infection and are very important for defense against mycobacterial infections T CELL NETWORK IL Network