It has become increasingly clear that the process of thymic education involves complex interactions between developing T lymphocytes and various stromal components of the thymus. In spite of the significant effort put forward understanding these interactions, the events which mediate this process remain ill defined. Most studies aimed at addressing these issues have been hampered, to a large extent, by the complexity of the thymus. This system can be best simplified by characterizing cell lines that function similarly to cells interacting in the thymus. Therefore, during the previous two years of funding we have established lines of T lymphocyte precursors and of cells inducing positive and negative selection. The primary goal of our research has been the definition of accessory cells that drive T lymphocyte development in the thymus. Their identification directly bears upon our understanding of mechanisms forming the T lymphocyte repertoire. Since we have shown that cultured fibroblasts induce positive selection, nd that peripheral B cells clonally delete auto-reactive thymocytes, we can no longer support hypotheses of thymic selection that are built around the premise of unique thymic AC. Therefore, models have to be favored which explain the paradox of thymic education on the basis of conventional ab-T lymphocyte interactions similar to those in the periphery. Thus, this research grant has been used to gain the information and to produce the tools to will be crucial to define how positive selection creates the repertoire of T lymphocyte specificities. More specifically it is proposed to characterize positive selection on fibroblasts, to determine how peptidic antigens influence the formation of the TCR repertoire, and to define peptides involved in positive selection. Thus, these studies are designed to learn how TCR-MHC interactions create the T lymphocyte repertoire.
