p53 Prevents maturation to the CD4+CD8+ stage of thymocyte differentiation in the absence of T cell receptor rearrangement

Abstract

Rearrangement of the immunoglobulin (Ig) and T cell receptor (TCR) gene loci allows for the generation of B and T lymphocytes with antigen-specific receptors. Complete rearrangement and expression of the TCR-β chain enables immature thymocytes to differentiate from the CD4+CD8+ to the CD4+CD8+ stage. Mice in which rearrangement is impaired, such as severe combined immunodeficient (SCID) mice or recombinase activating gene-deficient (RAG(- /-)) mice, lack mature B and T lymphocytes. Thymocytes from these mice are arrested at the CD4+CD8+ stage of T cell development. We previously observed that thymocytes from RAG-2(-/-) mice exposed to γ radiation differentiate from CD4-CD8- into CD4+CD8+ without TCR-β chain rearrangement. We now report that irradiated RAG-2(-/-) thymocytes undergo direct somatic mutations at the p53 gene locus, and that p53 inactivation is associated with maturation of RAG-2(-/-) thymocytes to the CD4+CD8+ stage. Generation of RAG-2(-/-) and p53(-/-) double-deficient mice revealed that, in the absence of TCR-β chain rearrangement, loss of p53 function is sufficient for CD4-CD8- thymocytes to differentiate into the CD4+CD8+ stage of T cell development. Our data provide evidence for a novel p53-mediated checkpoint in early thymocyte development that regulates the transition CD4- CD8- into CD4+CD8+ thymocytes.