The mTOR kinase determines effector versus memory CD8+ T cell fate by regulating the expression of transcription factors T-bet and Eomesodermin.
The mTOR kinase determines effector versus memory CD8+ T cell fate by regulating the expression of transcription factors T-bet and Eomesodermin.
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DOI：
10.1016/j.immuni.2009.10.010
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发表时间：
2010-01-29
期刊：
影响因子：
32.4
通讯作者：
Shrikant PA
中科院分区：
文献类型：
--
作者：
Rao RR;Li Q;Odunsi K;Shrikant PA
支持整合指令的机制，编程naïve CD8+ T细胞的效应和/或记忆分化尚不清楚。本文中，我们证明了IL-12是指导抗原刺激naïve CD8+ (OT-I) T细胞进行T-bet依赖的遗传性I型效应物成熟的关键决定因素，通过PI3K和STAT4途径增强和维持Ag/B7.1诱导的mTOR活性。通过雷帕霉素阻断mTOR活性可逆转IL-12诱导的遗传性I型效应功能，这是由于T-bet持续表达的丧失。值得注意的是，雷帕霉素处理IL-12条件下的OT-I细胞促进了Eomesodermin的持续表达，并产生记忆前体，在过继转移时表现出增强的维持和抗原召回反应。令人惊讶的是，记忆前体显示出比IL-12条件效应OT-I细胞更大的肿瘤功效。这些结果确定mTOR是CD8+ T细胞中决定效应细胞和/或记忆细胞命运的转录程序的“中心”调节因子。靶向mTOR活性为调节CD8+ T细胞介导的免疫提供了新的机会。
The mechanisms underpinning integration of instructions that program naïve CD8+ T cells for effector and/or memory differentiation are not well understood. Herein, we demonstrate that IL-12, the critical determinant that instructs antigen-stimulated naïve CD8+ (OT-I) T cells for T-bet dependent heritable type I effector maturation, enhances and sustains Ag/B7.1 induced mTOR activity via PI3K and STAT4 pathways. Blocking mTOR activity by rapamycin reverses IL-12 induced heritable type I effector functions due to loss of persistent T-bet expression. Remarkably, rapamycin treatment of IL-12 conditioned OT-I cells promotes persistent Eomesodermin expression and produces memory-precursors that demonstrate enhanced sustenance and antigen-recall responses upon adoptive transfer. Surprisingly, the memory-precursors show greater tumor efficacy than IL-12 conditioned effector OT-I cells. These results identify mTOR as the “central” regulator of transcriptional programs that determine effector and/or memory cell-fates in CD8+ T cells. Targeting mTOR activity offers new opportunities to regulate CD8+ T cell mediated immunity.
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DOI：
10.1084/jem.20021910
发表时间：
2003-05-05
期刊：
The Journal of experimental medicine
影响因子：
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