Essential Requirement for C-KIT and Common γ 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 γ chain (γ_c) is alymphoid because these receptors provide essential signals at the earliest stages of thymocyte development. The signals transduced by these receptors potentially regulate proliferation, survival, or differentiation, but the contribution of each receptor to distinct intracellular signaling cascades is only poorly defined. Here, we have examined whether enforced expression of Bcl-2 can rescue thymocyte development in c-kit and γ_c single or double mutant mice. A bcl-2 transgene (Eμ-bcl-2-25; expressed in the T cell lineage) was introduced into (a) c-kit and γ_c wild-type (c-kit⁺γ_c⁺bcl⁺), (b) c-kit–deficient (c-kit⁻γ_c⁺bcl⁺), (c) γ_c-deficient (c-kit⁺γ_c⁻bcl⁺), or (d) c-kit and γ_c double-deficient mice (c-kit⁻γ_c⁻bcl⁺). The bcl-2 transgene was functionally active in wild-type and c-kit or γ_c single mutants, as it promoted survival of ex vivo isolated thymocytes, including pro-T cells. In vivo, however, transgenic Bcl-2 did not release T cell precursors from their phenotypic block and failed to increase progenitor or total thymocyte cellularity in c-kit or γ_c single or double mutants. These data argue strongly against a role for Bcl-2 as a key mediator in signaling pathways linked to cytokine and growth factor receptors driving early thymocyte development.