Bcl-2 Does Not Rescue T Lymphopoiesis in Interleukin-7 Receptor Transgenic Mice (95.15)

Abstract

Abstract We have previously demonstrated that murine thymocytes down-regulate IL-7 sensitivity between the β-selection and positive selection checkpoints. To assess the consequences of enforced IL-7Rα expression during this developmental phase, we evaluated thymocyte IL-7 responsiveness in transgenic mice expressing the IL-7Rα gene under control of the lck proximal promoter. This model demonstrated that induction of ectopic high-level IL-7Rα expression during thymopoiesis increases the percentage of thymocytes responsive to IL-7 but results in an overall decrease in total thymic cellularity in transgenic mice. Transgenic thymocytes initiated IL-7Rα expression beginning in the DN2 compartment which was maintained through development to naïve peripheral subsets. Interference with thymocyte development became apparent shortly after initiation of transgene expression as there was an ~65% reduction in DN3 thymocytes in transgenic mice. This finding was reminiscent of phenotypes observed in IL-7 signaling-deficient mice insofar as there was a significant loss of pre-T cells, which correlated with a reduction in Bcl-2 expression. Indeed, lower Bcl-2 levels were observed in transgenic DN2 and DN3 thymocytes when assessed directly ex vivo. Additionally, and unlike the IL-7 signaling-deficient models, transgenic restoration of Bcl-2 expression did not correct the thymic hypocellularity induced by IL-7Rα overexpression. These data demonstrate that ectopic overexpression of the IL-7Rα past the pro-T stage interferes with DN3 thymocyte development and inappropriately maintains IL-7 responsiveness in β-selected thymocytes.