Peripheral T lymphocytes mediate antigen-specific immunity, and play regulatory roles in non-T cell immunity as well. T cells develop in the thymus, where they undergo multiple differentiative events yielding antigen-specific, self-MHC restricted cells. However, most thymocytes generated are not exported to the periphery, either because they fail to recognize self-MHC molecules (positive selection), or because they are not self-tolerant (negative selection). In addition, many express TCRs of no useful specificities; these are deleted by programmed cell death. Although death and positive selection thus shape the peripheral T cell repertoire, the nature of these events and their mechanisms are unclear. The studies proposed herein are directed towards gaining an understanding of these mechanisms. The first goal will be to define the developmental limits of the stages of maturity in which T cells are susceptible to positive selection. This will be accomplished by transplanting thymocytes, at defined stages and with known TCR specificities, into the appropriate selecting or non-selecting backgrounds, and analysing the progeny for generation of mature T cells. Subsets found to have positive selection potential will then be cultured in vitro in the presence of factors which may induce positive selection (i.e., antibodies to surface molecules, cytokines, or stromal cells), in an attempt to determine what factors are involved in this process. Both of the above studies are facilitated through the use of newly derived bcl-2 transgenic mice, in which developing T cells are resistent to the multiple forms of cell death which have previously hampered such investigations. Finally, the role of endogenous bcl-2 expression in programmed cell death and rescue among developing thymocytes will be analyzed. These studies will then be extended to include comparison of immature thymocyte turnover kinetics under conditions of nearly exclusive programmed cell death or death by negative selection, with or without inclusion of the bcl-1 transgene. Together, these studies should prove to be very beneficial in elucidating the mechanisms which shape the peripheral T cell repertoire.
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