The alloimmune response is a T cell dependent process mediated by either CD4+ or CD8+ T cells resulting in allograft rejection. Memory T cells jeopardize allograft survival as they have less stringent activation and survival requirements than their naive counterparts. Current clinical therapy in transplantation inhibits naive but not memory T cell responses. Thus, understanding the requirements for memory T cell generation, maintenance, homing and function is critical for the development of novel immunosuppressive modalities that interrupt memory T cell responses. Several studies propose the existence of secondary lymphoid organ resident 'central' (TCM) and non-lymphoid, peripheral tissue resident 'effector' (TEM) memory T cell subsets with distinct migratory and functional characteristics. Several controversies surround the origin, homeostasis, homing and function of these subsets. The candidate proposes to investigate these fundamental questions in vivo by adoptive transfer of CD8+ cell populations into wild-type hosts and alymphoplastic hosts lacking all secondary lymphoid organs. Preliminary studies presented show that: (1) In vivo models of generating alloreactive activated and memory T cells are well established; (2) activated T cells transition to memory T cells and mount allograft rejection in alymphoplastic hosts; (3) memory T cells are maintained long term in hosts lacking secondary lymphoid organs; and (4) in the alymphoplastic transplant model wherein an allograft can heal without immune attack, the homing of activated T cells is shown to be regulated by intragraft inflammation. Therefore, the origin, homeostatic maintenance, homing, and activation requirements of CD8+ central and effector memory T cell subsets will be addressed in wild-type and alypmhoplastic hosts. These experiments will further investigate the role of secondary lymphoid and non-lymphoid tissue environments in the differentiation and behavior of the two memory subsets. The proposed work will advance the applicant's skills in difficult cellular immunology techniques such as sorting, analyzing and tracking rare antigen-specific T cell populations in vivo; isolating and transplanting pancreatic islet cells; and isolating dendritic cells. The results of the proposed experiments will provide numerous possibilities for future career growth, enabling the candidate to compete and secure R01-type funding to become an independent investigator. The applicant will be extensively mentored in these efforts by Dr. Lakkis, whose consistent support and commitment will help the candidate secure several peer-reviewed publications during the award period. The candidate is committed to a physician-scientist career in transplantation immunology and nephrology and to pursuing fundamental immunology questions in memory T cell biology.