The population dynamics of T lymphocytes is an increasingly topical issue because of its important medical ramifications. An individual's pool of T cells is homeostatically regulated, integrating cell input, proliferation and death to maintain a remarkably constant total count. The focus of this proposal is maintenance of the naive T cell compartment, in particular the roles of T cell receptor (TCR) engagement of major histocompatibility complex (MHC) molecules and interleukin (IL)-7 receptor (R) binding of IL-7, both known to be required for na?ve T cells to persist for prolonged periods in the peripheral lymphoid organs. Performant systems permitting T cell-specific, tetracycline (tet)-regulatable expression of TCR and MHC class II molecules in mouso already exist, as does a protocol for monoclonal antibody blockade of IL-7R. These will be employed to 1) evaluate the interplay between TCR and IL-7R- mediated survival signals at the cellular level and 2) evaluate the interplay between TCR- and IL-7R-mediated survival signals at the molecular level. In addition, a novel system will be engineered in order to 3) generate, characterize and utilize mice expressing IL-7R on T cells in a tet-regulatable fashion. Specific hypotheses that will be addressed include the notion that the signaling pathways emanating from the TCR and IL-7R intersect and the speculation that IL-7R acts as a homeostatic sensor for the naive T cell compartment.
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