E2F1 and E2F2 are differentially required for homeostasis-driven and antigen-induced T cell proliferation in vivo
E2F1 and E2F2 are differentially required for homeostasis-driven and antigen-induced T cell proliferation in vivo
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DOI：
10.4049/jimmunol.175.2.647
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发表时间：
2005-07-15
影响因子：
4.4
通讯作者：
DeGregori, J
中科院分区：
文献类型：
--
作者：
DeRyckere, D;DeGregori, J
动态平衡驱动的T细胞增殖反应发生在淋巴细胞减少的环境中，并由TCR和IL-7信号介导。在这份报告中，我们证明了缺乏E2F1和E2F2的小鼠幼稚和记忆T细胞在淋巴细胞减少条件下的增殖缺陷，表明在动态平衡驱动的增殖过程中，E2F1和E2F2在TCR和/或IL-7信号的下游冗余地发挥作用。相反，T细胞对抗原刺激的增殖反应不受E2F1和EM缺失的影响(体内)或增强(体外)，这表明在不同刺激介导的T细胞增殖中对这些E2F因子的需求不同。E2F1/E2F2双基因敲除(DKO)T细胞在稳态信号作用下进入S期，但不能分裂，提示S期进程不完整或有缺陷。此外，E2F1/E2F2 DKO小鼠在暴露于亚致死剂量的辐射后不能恢复正常的T细胞数量，这表明这种由稳态驱动的增殖缺陷与生理相关。随着细胞周期进程的失败，DKO T细胞对动态平衡信号的反应明显减少，分化为记忆T细胞的能力显著降低。这些观察结果支持记忆T细胞的形成需要增殖的观点，并对临床策略的发展有意义，以最大限度地减少淋巴细胞减少诱导的自身免疫的发生。
Homeostasis-driven T cell proliferation occurs in response to a lymphopenic environment and is mediated by TCR and IL-7 signaling. In this report, we demonstrate a defect in the proliferation of murine naive and memory T cells lacking both E2F1 and E2F2 in response to lymphopenic conditions, suggesting that E2F1 and E2F2 function redundantly downstream of TCR and/or IL-7 signaling during homeostasis-driven proliferation. In contrast, T cell proliferation in response to antigenic stimulation is either unaffected (in vivo) or potentiated (ex vivo) by loss of E2F1 and EM, indicating divergent requirements for these E2F factors in T cell proliferation mediated by distinct stimuli. E2F1/E2F2 double knockout (DKO) T cells enter S phase in response to homeostatic signaling, but fail to divide, suggesting that S phase progression is either incomplete or defective. In addition, E2F1/E2F2 DKO mice do not recover normal T cell numbers following exposure to a sublethal dose of radiation, indicating that this defect in homeostasis-driven proliferation is physiologically relevant. Consistent with their failure in cell cycle progression, the differentiation of DKO T cells into memory T cells in response to homeostatic signals is significantly reduced. These observations support the idea that proliferation is required for memory T cell formation and also have implications for the development of clinical strategies to minimize the occurrence of lymphopenia-induced autoimmunity.