期刊
EUROPEAN JOURNAL OF IMMUNOLOGY
卷 40, 期 2, 页码 559-568出版社
WILEY-BLACKWELL
DOI: 10.1002/eji.200939736
关键词
p53; T-cell apoptosis and immune responses
类别
资金
- Medical College of Georgia Intramural Scientist Training Program
Mice 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 naive T cells from WT mice. In this report we show that, in response to TCR stimulation, T cells from naive 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.
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