Recently it has become clear that programmed cell death (also known as apoptosis) of T lymphocytes is regulated as tightly as is cellular activation and proliferation. Cell death is an essential event for T cells as decisions are made about thymocyte development. Additionally, mature T cells undergo apoptosis following their initial expansion to combat an inciting antigen. It has been shown also that apoptosis occurs as a means to ensure immune privilege in various tissues. Interestingly it appears that the mechanism by which T cells undergo apoptosis, either following initial immune expansion or when infiltrating immune privileged sites, involves an interaction between CD95 on the surface of T cells and CD95 ligand expressed on immune privileged tissues or on T cells themselves. While numerous studies have been published investigating the mechanism by which CD95 signal transduction regulates T cell apoptosis, little is yet known about how CD95 ligand expression is regulated. The overall goal of this proposal, therefore, is to begin an analysis of the transcriptional regulation of CD95 ligand in T cells as well as in a model system for immune privilege. To achieve this goal, three specific aims are presented. The first is to investigate signaling events which are causally related to expression and regulation of CD95 ligand at the level of gene transcription. Experiments for this aim involve those addressing what members of the MAP kinase family of protein kinases are important for TCR induced expression of CD95 ligand and to ask whether other molecules known to impact TCR mediated activation events also are important for regulation of this protein. Additionally, experiments in this aim, making use of a mouse made transgenic for a reporter construct including elements of the CD95 ligand promoter, are described to investigate regulation of this molecule in vivo. The second specific aim addresses the role of nuclear factor of activated T cells as well as other transcription factors in CD95 ligand regulation in T cells. The final specific aim address what transcription factors may be important for the regulation of CD95 ligand in the TM Sertoli cell line, a model for an immune privileged tissue. Collectively, it is hoped that these studies will provide insight into the regulation of expression of CD95 ligand and may help us learn how to modulate expression of this important molecule for potential therapeutic purposes.
