THE T-CELL RECEPTOR REPERTOIRE IN HUMAN-DISEASE

T-Cells recognize antigen via the T-cell antigen receptor (TcR). This step is fundamental to the generation of an antigen-specific immune re sponse, and leads to the activation of both cellular and humoral mecha nisms of immunity. The process of antigen recognition by T-Cells is th erefore a key step in the development of normal immunity and autoimmun e diseases. T-Cells have been implicated in the pathogenesis of autoim mune diseases such as multiple sclerosis, rheumatoid arthritis and thy roiditis, and in animal models of these diseases, disease can be trans ferred by antigen-specific T-cells. The recent interest in TcR usage i n human autoimmune diseases has arisen from the observations that ther e is a restricted usage of particular TcRs in a number of animal disea se models, and that therapy directed against the T-cell can lead to im provement of disease. The TcR molecule is a membrane-bound heterodimer which is expressed on the surface of the T-cell, in association with the CD3 complex of molecules. Two types of TcRs have been identified, an alpha beta heterodimer which is present on 95% of circulating T-cel ls, and a gamma delta heterodimer which is found on the remaining 5%. Both are very similar in structure, the alpha and gamma chains consist ing of variable (V), joining (J) and constant (C) domains, whilst the beta and delta chains have an additional diversity (D) domain between the V and J regions. The V, D and J domains confer antigenic specifici ty to the receptor. Each T-cell expresses only one type of receptor on its surface, with distinct V and J sequences, though the potential nu mber of TcRs that can be formed from its constituent genes is vast (fo r alpha beta receptors, it has been estimated that there may be up to 10(15) different receptors). How is this degree of diversity achieved? The TcR is encoded by genes which resemble those that encode immunogl obulin, and utilize similar mechanisms to generate diversity. Differen t gene segments which encode the V, D, J and C segments in the germlin e DNA recombine during T-cell development to form a rearranged gene. M ultiple V (approximate to 100 V alpha and approximate to 60 V beta) an d J segments are present in germ line DNA, and on the basis of sequenc e similarities, grouped into families (24 different V beta and 25 diff erent V alpha families are currently recognized). Furthermore, a proce ss of adding of nongermline encoded nucleotides to the junctions of th e rearranged segments during recombination contributes further to dive rsity. This review discusses the available techniques for analysing th e T-cell repertoire, the factors which affect the repertoire of mature T-cells in man, and the evidence that T-cell receptors and their gene s may play an important role in human diseases.