Down-modulation of tumor suppressor p53 by T cell receptor signaling is critical for antigen-specific T cell responses (IRM10P.737)

We report here that antigen-specific proliferative responses of naive and memory CD4 T cells require the down-modulation of tumor suppressor p53. In the absence of TCR signal, IL-2 induces a sustained increase in p53 protein, which prevents proliferative responses despite strong signaling through the IL-2 receptor. In contrast, TCR signaling results in early termination of p53 protein expression by decreasing p53 mRNA as well as by strong transcriptional induction of the p53-regulating protein Mdm2. Down-modulation of p53 in response to antigen stimulation is in fact critical for antigen-specific T cell proliferation; and preventing p53 degradation by inhibiting Mdm2 results in sustained p53 protein levels and prevents antigen-specific T cell proliferation. These studies elucidate a critical role of p53 as a negative regulator of T cell proliferation. It is the termination of p53 elevation by TCR signaling that allows proliferative responses to occur, enforcing antigen specificity.