Regulation of the TCRα repertoire by the survival window of CD4+CD8+ thymocytes

Abstract

T cell receptor (TCR) α alleles undergo primary and secondary rearrangement in double-positive (DP) thymocytes. By analyzing TCRα rearrangement in orphan nuclear receptor RORγ-deficient mice, in which the DP lifespan is shorter, and in Bcl-xL-transgenic mice, in which the DP lifespan is extended, we show that the progression of secondary Vα to Jα rearrangements is controlled by DP thymocyte survival. In addition, because Bcl-xL induces a bias towards 3′ Jα usage in peripheral T cells, we conclude that the programmed cell death of DP thymocytes is not simply a consequence of failed positive selection. Rather, it limits the progression of rearrangement along the Jα locus and the opportunities for positive selection, thereby regulating the TCRα repertoire.