Impact of cellular lifespan on the T cell receptor repertoire

Abstract

Pro-survival members of the Bcl-2 family are potent inhibitors of cell death and determine the lifespan of immature thymocytes by counteracting the intrinsically active apoptotic program in these cells. BH3-only proteins are potent antagonists of Bcl-2-like molecules and regulate death and survival of lymphocytes during their development and homeostasis. The intrinsic lifespan of CD4+8+ double-positive thymocytes was reported to actively shape the diversity of the immune repertoire, since mice overexpressing Bcl-XL were reported to show a bias towards the usage of distal 3′ Jα elements [1]. To gain support for this concept, we analyzed TCRα rearrangements in T lymphocytes that show an extended lifespan due to either loss of the BH3-only protein Bim or overexpression of Bcl-2. A minor but reproducible skewing towards the usage of the more distal 3′ Jα elements was observed in developing thymocytes and mature T cells from bim-/- and vav-bcl-2 transgenic mice, indicating that prolonged survival of double-positive thymocytes does have a significant impact on the selected TCRα repertoire. However, the changes that we observed were less pronounced than those found in lck-bcl-xL transgenic mice, pointing towards qualitative differences between Bcl-2- and Bcl-XL-mediated cell death inhibition during T cell development. © 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.