TY - JOUR
T1 - Defective T-cell receptor-induced apoptosis of T cells and rejection of transplanted immunogenic tumors in p53-/- mice
AU - Singh, Nagendra
AU - Huang, Lei
AU - Qin, Haiyan
PY - 2010/2
Y1 - 2010/2
N2 - 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 na?̈ve T cells from WT mice. In this report we show that, in response to TCR stimulation, T cells from na?̈ve p53-deficient mice exhibited higher proliferation and drastically reduced apoptosis than WT T cells. CD28 costimulation enhanced the proliferation of TCR-stimulated WTand 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.
AB - 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 na?̈ve T cells from WT mice. In this report we show that, in response to TCR stimulation, T cells from na?̈ve p53-deficient mice exhibited higher proliferation and drastically reduced apoptosis than WT T cells. CD28 costimulation enhanced the proliferation of TCR-stimulated WTand 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.
KW - T-cell apoptosis and immune responses
KW - p53
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U2 - 10.1002/eji.200939736
DO - 10.1002/eji.200939736
M3 - Article
C2 - 19950180
AN - SCOPUS:75149162515
SN - 0014-2980
VL - 40
SP - 559
EP - 568
JO - European Journal of Immunology
JF - European Journal of Immunology
IS - 2
ER -