T cell receptors Like B lymphocytes T cells express a clonal antigen-specific receptor. The T cell receptor (TCR) is in fact very similar to Immunoglobulin. It has 2 paired polypeptide chains both of which have constant and variable portions and both of which are composed of immunoglobulin-like domains. Two important differences are a) TCR is monovalent b) It exists only as a cell surface receptor and has no counterpart to secreted antibody. T cell development The accessory molecules CD4 and CD8 define the effector function and MHC restriction of a T cell. These molecules bind to MHC molecules at a different site to the TCR but form an important part of the TCR complex. In doing so they increase the affinity of interaction between the T cell and the APC and probably also contribute to the signalling mechanism required for T cell activation(see below). Immature thymocytes begin life as emigrants from the bone marrow. When they arrive in the thymus these precursors do not express CD4,CD8 or T cell receptor (TCR). CD4 and CD8 are very useful markers in thymocyte development and, since they express neither, these early thymocytes are said to be "double negative" cells. T cell development has many parallels with B cell development but there is one very important difference which is that the T cell repertoire is profoundly influenced by the MHC allotype of an individual through selection. Developing T cells (thymocytes) in fact undergo 3 different types of selection. The first critical stage in T cell development is the rearrangement of the T cell receptor beta chain (see below). This stage is very analogous to the rearrangement of the immunoglobulin heavy chain locus. As with the IgH locus the cell needs to make an in-frame functional rearranged TCRbeta chain to avoid death by apoptosis and to be given the signal to continue its development. Again, as with B cells, the cell senses when a functional TCRbeta chain is made by expressing surrogate partners which can pair with the rearranged chain to form a pre-T cell receptor complex. When a functional TCRbeta chain is made, these signals switch off beta chain rearrangement (thus providing allelic exclusion at the TCRbeta locus as well) and initiate a programme of differentiation which includes arrangement of the TCR alpha locus and expression of both the CD4 and CD8 molecules. Thus the first selective step in T cell development selects for a functional TCRbeta rearrangement and cells which successfully pass this scrutiny become CD4+CD8+ "double positive " cells.

The other two selective steps occur at the double positive stage of thymocyte development. First the mature T cell receptor must be expressed and this requires successful DNA rearrangement of the alpha chain locus. Once the mature TCR is expressed the TCR+ double positive thymocytes undergo two selective steps. These are called negative selection and positive selection. In negative selection clones bearing TCR which have a "high" affinity for self antigen are deleted, ie induced to undergo programmed cell death (apoptosis). In the context of TCR, self antigen means peptides from self proteins bound to MHC molecules. Negative selection has some parallel in B cell development and ensures self-tolerance. Positive selection is unique to T cells. While this process is not yet fully understood it appears that cells are selected for a "moderate" affinity for self MHC-peptide complexes. Added Value The currently favoured hypothesis is that expression of CD4 or CD8 is reduced, apparently at random, leaving CD4hiCD8lo and CD4loCD8hi thymocytes. Those CD4hi cells whose TCR interacts with self class II MHC/peptide complexes in the thymus, and those CD8hi, whose TCR interacts with class I MHC/peptide complexes, will be the only thymocytes to survive. The others will die by apoptosis. The surviving cells will complete the shut off of the irrelevant co-receptor, become mature single positive T cells and enter the peripheral circulation. Only about 2% of all double positive thymocytes survive the dual strictures of positive and negative selection. One prominent immunologist has described the role of thymocyte selection as "preventing the harmful and rejecting the useless" and it may help to view it in this light. Negative selection helps prevent autoimmunity, positive selection ensures that the peripheral T cells will be useful since cells which cannot recognise foreign antigenic peptides bound to self MHC cannot become activated in the periphery. The advantage of positive selection in shaping the mature T cell repertoire, and through this the immune response repertoire of the host, was discovered through MHC restriction.

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