Essential requirement for c-kit and common gamma chain in thymocyte development cannot be overruled by enforced expression of bcl-2

The thymus in mice lacking both the receptor tyrosine kinase c-kit and the common cytokine receptor gamma chain (gamma (c)) is alymphoid because these receptors provide essential signals at the earliest stages of thymocyte de velopment. The signals transduced by these receptors potentially regulate p roliferation, survival, or differentiation, but the contribution of each re ceptor to distinct intracellular signaling cascades is only poorly defined. Here, we have examined whether en forced expression of Bcl-2 can rescue th ymocyte development in c-kit and y, single or double mutant mice. A bcl-2 t ransgene (E mu -bcl-2-25; expressed in the T cell lineage) was introduced i nto (a) c-kit and gamma (c) wild-type (c-kit(+)gamma (+)(c)bcl(+)), (b) c-k it-deficient (c-kit(-)gamma (+)(c)bcl(+)), (c) gamma (c)-deficient (c-kit()gamma (-)(c)bcl(+)), or (d) c-kit and gamma (c) double-deficient mice (c-k it(-)gamma (-)(c)bcl(+)). The bcl-2 transgene was functionally active in wi ld-type and c-kit or gamma (c) single mutants, as it promoted survival of e x vive isolated thymocytes, including pro-T cells. In vive, however, transg enic Bcl-2 did not release T cell precursors from their phenotypic block an d failed to increase progenitor or total thymocyte cellularity in c-kit or gamma (c) single or double mutants. These data argue strongly against a rol e for Eel-2 as a key mediator in signaling pathways linked to cytokine and growth factor receptors driving early thymocyte development.