CD8 T cells are essential for clearance of intracellular pathogens. A current goal of vaccinology is to develop methods for inducing protective T cell mediated responses against some of the world's most intractable infectious diseases, including malaria and the human immunodeficiency virus. Effective vaccination requires the generation of long-lived memory cells with protective capabilities. Induction of a productive CD8 T cell response to robust infections represents a best case scenario but such models have yielded valuable insight into the regulation of memory CD8 T cell development. Thus far, vaccines geared toward promoting CD8 T cell immunity have generally not met with success. Therefore, identifying the checkpoints in memory CD8 T cell development along with the elements controlling those checkpoints continues to represent an important research goal. Our studies have focused on the detailed analysis of the factors that control the generation of central and effector memory CD8 T cells in response to bacterial and viral infections. Our results along with those from a number of other groups, have shown that activation of na?ve CD8 T cells in response to infection results in the generation of a heterogeneous population of effector cells with distinct phenotypic and functional properties. Our preliminary and published data supported by this long-standing grant, indicate that a population of early effector cells (EEC) are the sourc of the two major effector subsets: memory-precursor effector cells (MPEC), which generate memory cells, and short-lived effector cells (SLEC) which, at least in a primary response, are a terminal lineage. This proposal is aimed at exploring the central hypothesis that commitment to the memory lineage is designated at the EEC stage and further that EEC are themselves heterogeneous with respect to their developmental potential. This hypothesis will be examined in three specific aims:
Aim 1. To determine the developmental potential of EEC in response to the external milieu.
Aim 2. To identify the metabolic pathways in early effector cells leading to memory development.
Aim 3. To identify the molecular pathways that specify effector subset lineage development.
CD8 T cells are required to protect against infectious pathogens. Vaccines aimed at promoting CD8 T cell mediated immunity are now being developed. The early events leading to the development of protective CD8 T cell memory are poorly understood and these studies will address that problem.
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