BY Dr. Dhafer Abdullah Farhan Ph. D. Cancer research
Today We are hereList of abbreviations
IntroductionAdaptive immune responses have been subdivided into: Humoral (antibody- mediated) immune responses. Cellular (cell-mediated) immune responses.
* Host defenses against extracellular infections are mediated by: - Antibody - Complement - Macrophages * Intercellular infections are mediates by CMI * CMI are responsible for: - Resistance to intracellular pathogens - Resistance to fungal and protozoal infections - Resistance to tumors
Cell Mediated Immunity
Many microbes have developed mechanisms that enable them to survive and even replicate within phagocytes, so the innate immunity is unable to eradicate infections by such microbes. In CMI against phagocytosed microbes, the specificity of the response is due to T cells – but the actual effector function is mediated by the phagocytes.Cell-mediated immunity
It is an immune response that does not involve antibodies.It occurs inside infected cells and is mediated by T lymphocytes. The pathogen's antigens are expressed on the cell surface or on an antigen-presenting cell. Helper T cells release cytokines that help activated T cells bind to the infected cells’ MHC-antigen complex and differentiate the T cell into a cytotoxic T cell. The infected cell then undergoes lysis.Characters Of CMI
Cellular immune response is mediated by: - Subpopulation of T-lymphocytes - Macrophages and their productsCD4+ TH1 cells and CD8+ T cells recognize class II MHC-associated or class I MHC-associated peptide antigens of phagocytosed microbes, respectively, and produce cytokines (IFN-g, TNF) that activate the phagocytes to kill the microbes and stimulate inflammation.
Cell-mediated cytotoxicity
It is an essential defense against intracellular pathogens, including viruses, some bacteria and parasites, tumor cells and even cells of the body. In addition, the process is important in the destruction of allogeneic tissue grafts.Several types of cells can execute this activity including T-cytotoxic (Tc) cells, NK-cells and sometimes myeloid cells.
Cellular immunity protects the body through:
Tc-cells recognize specific Ag presented by MHC-I. Most Tc are CD8+ve, but about 10% of MHC-restricted cytotoxic T-cells are CD4+ve & recognize Ag presented on MHC-II.Tc-cells and NK-cells act in a complementary way to protect the body.
The TCRs and CD8 molecules on the surface of naive T8-lymphocytes are designed to recognize peptide epitopes bound to MHC-I molecules on antigen-presenting cells or APCs . The TCRs and CD8 molecules on the surface of cytotoxic T-lymphocytes (CTLs) are designed to recognize peptide epitopes bound to MHC-I molecules on infected cells and tumor cells.NK-cells Recognize cells which fail to express MHCI molecules. They can also bind to Ab already attached to Ag an a target cell, using their Fc-R (CD16), in a what is known as AB-dependent cell-mediated cytotoxicity (ADCC).
Several viruses have evolved mechanisms to avoid recognition by Tc cell. They reduce the expression of MHC molecules or even produce proteins which divert MHC molecules out of the endoplasmic reticulum. So NK-cells specifically recognize cells which have lost their MHC - I molecules.
Mechanisms of cell-mediated cytotoxicity
Tc, NK- and K-cells use variety of different mechanisms to kill their targets, including: * direct cell-cell signaling via surface molecules. * indirect signaling via cytokines. in addition many CD8 Tc and large granular lymphocytes (NK and K-cells) have granules which contain proteins that damage target cells if they are released directly against the target cell plasma membrane.A cytotoxicity which may be signaled via Fas or a TNF-R on a target cell. Tc cells signal to their targets using members of TNF-R group of molecules. These include Fas (CD95) and the type-1 TNF-R (TNFR-1) which are widely distributed in the body. CD8+ T cell can kill the infected cells is via Fas/FasL interactions. Activated CD8+ T cells express FasL on the cell surface, which binds to its receptor, Fas, on the surface of the target cell. This binding causes the Fas molecules on the surface of the target cell to trimerise, which pulls together signalling molecules. These signalling molecules result in the activation of the caspase cascade, which also results in apoptosis of the target cell.
** Most CD8 TC and NK-cells (and macrophages) have vesicles containing TNF and lymphotoxin which can be released onto a target cells. TNF acts in a very similar way to the Fas-ligand. It causes trimerization of the TNFR-1 so that the receptor associates with adaptor proteins which recruit caspases. Both TNFR-1 and Fas containing intracytoplasmic domains (death-domains) which are found on a number of proteins involved in cell survival.
*** The specific granules of NK-cells and Tc contain several proteins, including perforin and granzymes (granules associated enzymes). After binding to its target, the Tc cells directs its granules towards the membrane a joining the target. Then, in a Ca-dependent phase, the granule contents are discharge into the cleft between the two cells. Perforin is a pore-forming proteins and in the presence of Ca , the perforin bind to the target cell membrane and polymerize to form transmembrane channels. Tc-protected from autodestruction with this protein by a proteoglycan (chondroitin-sulphate A) which may bind to and inactivate the perforin, thus Tc-survives and can continue kill further targets. Granzymes are collection of serine estrases (enzymes) which are also released upon granule exocytosis and become active after release. Some of these enzyme trigger apoptosis and DNA-degradation. Both perforin and granzymes act synergistically; the granzymes enter the target cells via pore created by perforin.
To summarize the lymphoid cytotoxic effectors: CD8 Tc use both Fas- L and granule release to kill their targets. CD4 Tc-cells use principally FasL, and NK-cells use primarily their granules. TNF may contribute to the cytotoxic damage produced by any of these cells.
*Cytotoxicity may be triggered specifically to a target by ADCC or may involve a range of non-specific toxic mediators. Macrophage and neutrophil express Fc-gR1&2 which allow them to engage their targets by ADCC.` ** Macrophages and neutrophils granules which contain neutrophil defensins, lysosomal enzymes and cytostatic proteins. If the phagocyte fails to internalize its target, then these mediators may be released into the extracellular environment and contribute to localized cell damage ((frustrated phagocytosis)), the effect of these mediators tends to produce necrosis and inflammation. *** Activated macrophage secrete TNF which can induce apoptosis in a similar way to lymphoid cytotoxic effectors.