C-Myb is a novel regulator of Bcl-xL in the CD4+ and CD8+ double positive stage of T cell development (85.2)

Abstract

Abstract The lifespan of quiescent CD4+ and CD8+ double positive (DP) thymocytes regulates the composition of the peripheral T cell repertoire. However, the molecular mechanisms controlling DP thymocyte survival remain poorly understood. The c-Myb transcription factor is highly expressed in quiescent pre-selection DP thymocytes. Using a conditional deletion mouse model, we demonstrate that pre-selection DP thymocytes lacking c-Myb undergo premature apoptosis due to decreased expression of the key anti-apoptotic factor Bcl-xL. Moreover, c-Myb deficient DP thymocytes display a skewed TCRα repertoire, with a bias towards 3' Jα?usage, as a consequence of premature apoptosis occurring shortly after the initiation of TCRα rearrangements in vivo. Finally, re-introduction of c-Myb to c-Myb deficient DP thymocytes restored control levels of Bcl-xL mRNA and protein. Taken together, our study identifies c-Myb as a novel regulator of Bcl-xL expression in the DP stage of T cell development. We demonstrate that c-Myb acts through a novel pathway, independently of RORγt and TCF-1, two transcription factors previously shown to promote Bcl-xL expression in DP thymocytes. This study sheds new light on the regulation of the survival of pre-selection DP thymocytes and provides a novel mechanism by which c-Myb guards the balance between life, death and differentiation during hematopoiesis.