MHC and T cell development.

The ability to discriminate self from non-self is a fundamental property of the immune system. In the case of T lymphocytes, the first level of this discrimination takes place in the thymus, where most lymphocytes carrying an alphabeta T cell receptor (TCR) become tolerant to self-epitopes represented within the thymic microenvironment and differentiate into CD4+ or CD8+ single positive thymocytes. In the periphery, these subsets correspond respectively to helper and cytolytic lymphocytes able to react to non-self antigens presented in the context of MHC class II and I molecules. Apart from an early phase, the development of alphabeta T cells is based on a TCR-MHC interaction which is allele-specific and, depending on its nature, leads to either protection from apoptosis and maturation (positive selection) or physical elimination of thymocytes (negative selection). Thus, these positive and negative selection processes concomitantly allow the rescue of the useful fraction and the elimination of the potentially harmful fraction of the TCR repertoire. Recent advances have provided important elements for the comprehension of the development of alphabeta T cells. In accordance with previous in vitro studies related to differentiation of CD8+ thymocytes, in vivo derived data have established that the positive selection of CD4+ thymocytes is a peptide-specific process: it is based on the intrathymic TCR recognition of self-peptide:self-MHC molecular complexes. Despite this fact, it is now clear that the TCR reactivity to non-self MHC molecules or alloreactivity--a major characteristic of the mature TCR repertoire--does not result from intrathymic T cell selection, but rather is an intrinsic property of germline-encoded TCR domains. Finally, a significant number of experiments indicate that, in secondary lymphoid organs, a repeated TCR-MHC low affinity interaction is required to maintain the mature peripheral T cell pool and therefore the mature TCR repertoire. Such a TCR-MHC interaction-induced protection from apoptosis is remarkably reminiscent of the intrathymic positive selection phenomenon. Thus, the role of self-MHC recognition in TCR repertoire development and survival may account for the influence of MHC genotype on susceptibility to specific autoimmune diseases.