Theophylline alleviates cyclophosphamide-induced T cell senescence by downregulating acetylation of p53 at lysine 373.

Cyclophosphamide is a widely used immunosuppressive and chemotherapeutic agent in clinics. Previous studies have indicated that cyclophosphamide treatment induces cellular senescence in patients, although the underlying mechanisms remain elusive. Here, we reported that cyclophosphamide induced T cell senescence in the spleen of mice. Meanwhile, phosphoramide mustard cyclohexanamine (PM), an active metabolite of cyclophosphamide, triggered human T cell senescence. RNA sequencing analysis revealed that PM promoted senescence of primary human T cells through the activation of the p53 signaling pathway. Moreover, PM strongly increased the acetylation of p53 lysine 373 in T cells. Compared with the wild-type p53, mutating lysine 373 of p53 to arginine markedly reduced the p21 and p16 expression in PM treated Jurkat cells. Notably, we found that theophylline, an activator of histone deacetylase HDAC, ameliorated the senescence phenotype of both primary human T cells induced by PM and splenic T cells induced by cyclophosphamide in mice. Together, the results from current study could provide a potential strategy against cyclophosphamide-induced T cell senescence by inhibiting p53 acetylation.