Tumor suppressor p53 controls thymic NKT17 development

Abstract

ABSTRACTThe tumor suppressor p53 antagonizes tumorigenesis, notably including the suppression of T cell lymphomas while its role on physiological T cell biology including thymic T cell development has not been fully understood. Invariant natural killer T (iNKT) cells develop in the thymus as innate-like αβ-T cells which consist of NKT1, NKT2 and NKT17 subsets. We found that the tumor suppressor p53 regulates specifically thymic NKT17 development. p53 is highly expressed in NKT17 relative to other T cell populations. Loss of p53 in the T cell lineage resulted in increased thymic NKT17 cell number with retention of lineage specific cytokine production, while development of NKT1, NKT2 and conventional T cells was not affected. Of interest, γH2AX expression was higher in NKT17 than NKT1 and NKT2 at steady state, and it was further increased in p53-deficient NKT17, suggesting that NKT17 development involves selectively greater DNA damage or genomic instability and that p53 expression might be in response to these damage signals. Taken together, our results indicated that the tumor suppressor p53 is active in selectively controlling thymic NKT17 development, with absence of p53 leading to an increase in thymic NKT17 cells expressing high levels of DNA damage response.