p53 regulates thymic Notch1 activation

Notch is crucial for multiple stages of T cell development, including the CD4(+)CD8(+) double positive (DP)/CD8(+) single positive (SP) transition, but regulation of Notch activation is not well understood. p53 regulates Presenilin 1 (PS1) expression, and PS1 cleaves Notch, releasing its intracellular domain (N-IC), leading to the expression of downstream targets, e.g. the HES1 gene. We hypothesize that p53 regulates Notch activity during T cell development. We found that Notch1 expression and activation were negatively regulated by p53 in several thymoma lines. Additionally, N-IC was elevated in Trp53(-/-) thymocytes as compared to Trp53(+/+) thymocytes. To determine if elevated Notch1 activation in Trp53(-/-) thymocytes had an effect on T cell development, CD4 and CD8 expression were analyzed. The CD4(+) SP/CD8(+) SP T cell ratio was decreased in Trp53(-/-) splenocytes and thymocytes. This alteration in T cell development correlated with the increased Notch1 activation observed in the absence of p53. These data indicate that p53 negatively regulates Notch1 activation during T cell development. Skewing of T cell development toward CD8(+)SP T cells in Trp53(-/-) mice is reminiscent of the phenotype of T-IC-overexpressing mice. Thus, we suggest that p53 plays a role in T cell development, in part by regulating Notch1 activation.