Transplantation is the preferred method of treatment for many forms of end-stage organ failure. Current therapy in clinical transplantation relies on potent non-specific immunosuppressive drugs to inhibit rejection. While short-term results have improved, long-term outcomes remain inadequate. Furthermore, patients must adhere to life-long treatment regimens that dramatically increase the risks of cardiovascular disease, infections and malignancies. Strategies to promote the acceptance of allogeneic tissues without the need for chronic immunosuppression could reduce the risk of these life-threatening complications and expand the application of organ, tissue and cellular transplantation. The unifying hypothesis and theme of this program is that donor-specific memory T cells generated during protective immune responses against environmental pathogens constitute an important barrier to tolerance induction in adults. Accordingly, this program will be comprised of four inter-related projects. The first Project will explore interaction between viral infection, protective immune responses and tolerance induction to alloantigens. The second Project will determine the number, subset and phenotype of allospecific memory T cells that prevents the induction of tolerance and define strategies to tolerize allospecific CD4 and CD8 memory populations. The third Project will test the hypothesis that the transition of activated T cells to memory is an instructional process which requires the presence of cytokines that inhibit activated T cell proliferation and apoptosis. Finally, the fourth project will define the mechanisms that regulate commitment of native CD4 and CD8 T cells to proliferate and differentiate into effector and memory T cells and identify differences in the activation programs of nave versus memory T cells The knowledge gained through these studies will facilitate development of tolerance induction protocols that are efficacious, safe, and clinically applicable.