T-cells are MHC-Restricted - Essay Example

T-cells are MHC-Restricted T-cells are a member of the subset of white blood cells called lymphocytes. These cells, which originate in the thymus, play a vital role in cell-mediated immunity. The T-cell can be distinguished from other lymphocytes such as Natural Killer (NK) cells and B-cells due to the presence of the T-cell receptor (TCR) which is found only on the surface of T-cells. There are two principal forms of T-cells. These are CD4+ T-helper cells, and CD8+ T-cytotoxic cells. Each of these is named for the presence of CD4 and CD8 receptors on the surface of each cell type, and also according to the role they play in the immune system. T-helper cells are so named because they produce and secrete protein molecules called cytokines that perform various functions within the immune system that direct and 'help' the immune response. Within the Helper T-cell group are two further subsets known as Th1 (or type 1) and Th2 (or type 2). Cytotoxic T-cells play a central role in the destruction of tumour cells and virally-infected cells, and are also thought to have an important role in transplant rejection. Differentiation of T-cells into CD4+ and CD8+ cells begins in the thymus during T-cell development. However, cells only become fully differentiated mature cells in the peripheral lymphoid system, during an active immune response. All T-cells originate in the marrow of long bones (such as the femur), and are derived from hematopoetic stem cells. Hematopoetic progenitors that derive from these stem cells travel to the thymus via the lymphatic system. Upon reaching the thymus they divide to generate T-cell precursors known as immature thymocytes (Schwarz B A, Bhandoola A. 2006). Approximately 98% of these precursor cells die in the thymus without becoming fully-differentiated T-cells, due to selection processes called positive and negative selection. The 2% of cells that survive selection eventually leave the thymus to become mature T-cells. At the beginning of the selection process, all thymocytes are termed 'double positive'. As these cells begin to develop they move deep into the cortex of the thymus. There they are presented with self-antigens derived from the host. These self-antigens are presented on Major Histocompatibility Complex (MHC) molecules that are located on the surface of cortical epithelial cells. Thymocytes that bind the MHC-antigen complex with sufficient affinity (binding strength) are allowed to survive and move to the next stage of development. Thymocytes which do not bind with adequate affinity receive a chemical signal which causes them to undergo apoptosis, a process also known as programmed cell death, in which cells die in a way that cannot cause harm to the host. This first round of selection is called positive selection, because cells which bind with affinity are allowed to survive. During this process another type of selection occurs: cells which bind with MHC class II molecules develop into CD4+ cells, and cells which bind with MHC class I molecules develop into CD8+ cells. Those cells that survive the first round of selection migrate to the boundary between the cortex and medulla of the thymus. In the medulla, they are presented again with MHC molecules that present self-antigens. This time, the complex is presented by dendritic cells and macrophages, two types of antigen-presenting cells. In this situation, cells which bind with very strong affinity receive a death-inducing signal, and undergo apoptosis, while cells that do not bind with strong affinity are allowed to survive and continue development. It is at this stage, called negative selection, that the majority of developing T-cells die. Negative selection is a particularly important part of the development process, as it prevents the development of T-cells which react to self-antigens, and thus prevents the development of auto-immune disease (Baldwin TA, 2004). The cells that survive both positive and negative selection are mature nave T-cells, which then leave the thymus and begin to circulate in the lymphatic system. A small amount of cells undergo a further selection process and become regulatory T-cells. The Major Histocompatibility Complex (MHC) is a set of molecules displayed on the surface of all cells. This complex is responsible for antigen presentation and allows lymphocyte recognition of antigens which are present in the cell. MHC molecules play a central role in the control of the immune response, because these molecules present antigens derived from both self and non-self proteins. This makes the MHC an important target in controlling transplant rejection as well as the regulation of the immune system. In humans, these molecules are called Human Leukocyte Antigens (HLA), while in the mouse they are known as H-2 antigens. For both species, they are encoded by a set of genes called Major Histocompatibility Complex genes. MHC class II is expressed constitutively on dendritic cells, thymic epithelial cells and B-cells, and its expression can also be induced on T-cells and macrophages. MHC class I is expressed on all nucleated cells in varying amounts. For example, leukocytes have the highest expression rate of MHC class I, while neural cells have the lowest rate of expression. While the mechanism of T-cell activation varies among the different T-cell types, the 'two-signal model' of CD4+ T-cells applies in most cases. CD4+ T-cell activation occurs when both the T-cell receptor and another receptor called CD28 on the surface of the T-cell are engaged by the MHC and members of the B7 receptor family, respectively, on the surface of an antigen presenting cell. An effective immune response requires stimulation of both the T-cell receptor and CD28. The binding of the T-cell receptor to an MHC-antigen complex provides the first signal that is required. This requirement ensures that only T-cells with a receptor that is specific to the peptide antigen are activated. The second signal is non-specific, and only requires an interaction between CD28 on the T-cell and B7 on the antigen-presenting cell. The cell presenting the antigen is typically a 'professional' antigen presenting cell; for a nave T-cell (one that has not 'seen' antigen before) this is usually a dendritic cell, however macrophages and B-cells can stimulate mature T-cells. Phagocytes are unable to detect infected cells, and antibody cannot enter them, so CD8+ cytotoxic T-cells play a crucial role in detecting and destroying these cells. CD8+ cells become activated to destroy infected cells when their receptors recognise endogenous antigen presented on MHC class I molecules of those infected cells. All T-cells are MHC-restricted in terms of their ability to see antigens. This means they only recognize peptides that are presented on 'syngeneic' (self) MHC by antigen-presenting cells. CD4 T-cells recognize exogenous antigen presented on MHC II molecules by dendritic cells, macrophages, and C-cells, while CD8 T-cells recognize antigen presented on MHC class I molecules by cells which are infected with endogenous pathogens. In contrast to B-cells, T-cells do not directly recognize antigens, and in fact T-cells are unable to recognize whole proteins or any non-protein antigens (such as carbohydrates). Instead, they can only detect antigen when it is complexed with MHC molecules. The MHC can bind only very small peptides, of between seven and fifteen amino acids in length, therefore the T-cells themselves only recognize antigen in the form of these peptides. Cells which present antigen to CD4 cells do so by taking up antigen and degrading it into peptides which are of the right length to be presented by MHC molecules in the antigen-presenting groove. (Decker Janet M, 2006) Each class of MHC molecule presents a particular type of antigen. MHC class I molecules present endogenous antigen, which is derived from within the cell. MHC class II molecules present antigens which are derived extracellularly. Because CD8+ T-cells recognize only MHC class I, and CD4+ T-cells recognize only MHC class II, each type of cell works within a particular arm of the immune response. CD8+ cells are activated by pathogens which infect cells (such as viruses) while CD4+ cells are activated by extracellular pathogens (typically bacteria). During thymic development, T-cells are selected to recognize only self MHC when complexed with non-self antigens. However, up to 5% of T-cells are able to respond to allogeneic (non-self) MHC. It is these alloreactive cells which are responsible for rejection of donor organs and tissues when donor and recipient MHC loci are mismatched. As well as MHC class I and II, minor histocompatibility antigens are able to induce a weak rejection response, which may be tissue-specific or sex-specific. (Decker Janet M, 2006) There is a known genetic link between Human Leukocyte Antigen type and a number of diseases. One of these is insulin-dependent (Type 1) diabetes, which is four times as frequent in people with an allele known as HLA-DR4. People who express the HLA-A3 allele are seven times more likely to have excessive iron levels, and this allele is also linked to an increased likelihood of developing spinal ankylosing spondylitis. It is thought that such conditions occur due to defective thymic development in which T-cells which are able to react to self-antigen are not deleted during negative selection. Bare Lymphocyte Syndrome is a partial of complete lack of MHC class I or class II proteins. People with this condition are more susceptible to opportunistic infections and viral infections. Depending on the ability of the individual to express MHC, they may experience symptoms ranging in severity, from a lack of either a type 1 or a type 2 immune response, to Severe Combined Immuno-Deficiency, in which they cannot effectively mount either type of response. (Decker J, 2006) A 1993 study by Zhang et. al. found that clonotypic interactions that regulate auto-reactive T-cells can be induced by T-cell vaccinations. In this study, patients with multiple sclerosis were vaccinated with irradiated self-derived regulatory T-cells that were reactive to myelin basic protein. CD8 cell specificity was ensured via MHC restriction. T-cell responses were then induced in an attempt to deplete the recipients' own MBP-reactive T-cells, and prevent auto-reactive cells from destroying the protein. In 2001, Rau et. al. investigated CD8 cell function in Xenopus frogs, using several techniques including antibody depletion, skin allografts, and tumour transplantation. Adult frogs were injected with anti-Xenopus CD8+ monoclonal antibodies to deplete CD8+ cells. The injected frogs displayed impaired immune responses to transplanted syngeneic tumours, as well as delayed rejections of MHC-disparate skin grafts. This was the first positive indication that CD8 T-cells are involved in acute skin allograft rejection, and also suggests that (in this frog species, at least) T-cells which express CD8 epitopes may be involved in anti-tumour responses that are MHC-unrestricted. References: Baldwin TA, Hogquist KA, Jameson SC, (2004) The fourth way Harnessing aggressive tendencies in the thymus. "J Immunology." 173:6515-20, 2004. http://www.jimmunol.org/cgi/content/full/173/11/6515 Decker Janet M., PhD (2006) MHC: Antigen Processing and Presentation http://microvet.arizona.edu/Courses/MIC419/Tutorials/MHC.html jdecker@u.arizona.edu February 17, 2006 Rau L, Cohen N, Robert J. (2001) MHC-restricted and -unrestricted CD8 T cells: An evolutionary perspective. Department of Microbiology and Immunology, University of Rochester Medical Center, Rochester, NY 14642, USA 2001 Dec 15;72(11):1830-5. PMID: 11740396 [PubMed - indexed for MEDLINE] Schwarz BA, Bhandoola A. (2006) trafficking from the bone marrow to the thymus: a prerequisite for thymopoiesis. Immunology Rev 209:47, 2006. Zhang J, Medaer R, Stinissen P, Hafler D, and Raus J (1993) MHC-restricted depletion of human myelin basic protein-reactive T cells by T cell vaccination Multiple Sclerosis Research Unit, Dr. L. Willems Instituut, Diepenbeek, Belgium. Science, Vol 261, Issue 5127, 1451-1454 Copyright 1993 by American Association for the Advancement of Science Read More