The mechanisms that integrate the signals delivered through the TCR and cytokine receptors for the differentiation and proliferation of T cells are incompletely understood. In Immunity, Hodes and colleagues show that the transcriptional regulator p53 is needed to integrate IL-2-induced proliferation in the context of an antigen-specific response in both naive CD4+ T cells and memory CD4+ T cells. While wild-type CD4+ T cells require signaling from both the TCR and IL-2 for proliferation, p53-deficient CD4+ T cells undergo abundant proliferation in response to IL-2 alone. Stimulation of T cells with IL-2 in the absence of TCR signaling induces sustained p53 expression, while costimulation via the TCR terminates the initial increase in p53 protein via a decrease in p53 mRNA and induction of the ubiquitination and proteosomal degradation of p53 mediated by the E3 ubiquitin ligase Mdm2. Downregulation of p53 is required for TCR-induced proliferation, which suggests a central role for p53 in controlling antigen-specific CD4+ T cell responses.

Immunity 40, 681–691 (2014)