During differentiation in the thymus, T cells develop the receptor repertoire which allows them to recognize antigen in the context of self major histocompatibility complex (MHC) molecules. Thymic MHC-encoded determinants greatly influence the selection of the T-cell receptor repertoire. Both positive and negative selection is thought to occur in the thymus, but how this """"""""education"""""""" occurs is not well understood. It has been suggested that an interaction between the T-cell receptor (TCR) and MHC-encoded determinants occurs, leading to the selection of an MHC-restricted receptor repertoire. Our work has confirmed this hypothesis, and is currently focusing on the additional role that CD4- MHC and CD8- MHC interactions exert on the selection process. Repertoire analysis is performed by testing for expression of V-regions of particular TCR-chains that can be identified with monoclonal antibodies. Expression of these chains is associated with recognition of particular MHC antigens, while deletion of T cells with these TCR's occurs when other defined MHC antigens are expressed. Extrathymic T-cell repertoire development is also being analyzed using the models of neonatally thymectomized mice and nude mice. Such an analysis has yielded important answers to the questions of how the thymus affects tolerance induction, but also yield insights into the generation of the thymus-independent T-cell repertoire. This pathway of development appears to be a prominent one, especially in adult patients after bone marrow transplantation. The significance of this project lies in: (1) understanding the factors that control development of T cells; and (2) applying this knowledge to restoring T cells after bone marrow transplantation and controlling tolerance induction.
