AbstractMice lacking the tumor suppressor gene p53 spontaneously develop T‐cell lymphomas at a high rate, suggesting that in these mice lymphomas arise due to defective apoptosis mechanisms in T cells mediated by p53. However, a role of p53 in regulation of T‐cell responses or apoptosis has been poorly defined. TCR‐mediated signaling in the absence of CD28 costimulation induces both apoptosis and proliferation of naïve T cells from WT mice. In this report we show that, in response to TCR stimulation, T cells from naïve p53‐deficient mice exhibited higher proliferation and drastically reduced apoptosis than WT T cells. CD28 costimulation enhanced the proliferation of TCR‐stimulated WT and p53−/− T cells, suggesting that p53 uncouples CD28‐mediated antiapoptotic and proliferative signals. To evaluate the physiological significance of these findings, we transplanted OVA expressing‐EG.7 tumor cells into WT and p53−/− mice. Unlike WT mice, p53−/− mice exhibited a robust tumor‐resistant phenotype and developed cytotoxic T‐cell responses against OVA. Collectively, these data support the hypothesis that p53 is an essential factor in negative regulation of T‐cell responses and have implication for immunomodulation during treatment of cancers and other inflammatory conditions.