mTOR regulates memory CD8 T-cell differentiation.
mTOR regulates memory CD8 T-cell differentiation.
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DOI：
10.1038/nature08155
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发表时间：
2009-07-02
期刊：
影响因子：
64.8
通讯作者：
Ahmed, Rafi
中科院分区：
文献类型：
--
作者：
Araki, Koichi;Turner, Alexandra P.;Shaffer, Virginia Oliva;Gangappa, Shivaprakash;Keller, Susanne A.;Bachmann, Martin F.;Larsen, Christian P.;Ahmed, Rafi
记忆性CD8 T细胞是保护性免疫的重要组成部分，诱导有效的记忆性T细胞反应是抗慢性感染和肿瘤疫苗的主要目标。在设计能够增加记忆反应强度的疫苗方案方面已经付出了相当大的努力，但在开发提高记忆T细胞功能质量的策略方面却很少得到重视。在这项研究中，我们发现雷帕霉素的哺乳动物靶点mTOR是记忆性CD8 T细胞分化的主要调节因子，与我们预期的mTOR特异性抑制剂雷帕霉素（一种免疫抑制药物）相反，mTOR特异性抑制剂雷帕霉素对记忆性CD8 T细胞的产生具有令人惊讶的免疫刺激作用。急性淋巴细胞性脉络丛脑膜炎病毒（LCMV）感染后用雷帕霉素治疗小鼠，不仅增加了病毒特异性CD8 T细胞的数量，而且提高了其质量。用不复制的VLP疫苗免疫小鼠后也观察到类似的效果。此外，雷帕霉素治疗还增强了接种MVA（修饰痘苗病毒-安卡拉）后非人灵长类动物的记忆T细胞反应。雷帕霉素在T细胞反应的扩张期和收缩期都有效；在扩张期，它增加了记忆前体的数量，在收缩期（效应到记忆过渡），它加速了记忆T细胞分化程序。利用RNAi抑制抗原特异性CD8 T细胞中mTOR、raptor或FKBP12表达的实验表明，mTOR本质上通过mTORC1通路调节记忆性T细胞分化。因此，这些研究确定了调节记忆形成的分子途径，并为提高疫苗或感染诱导的记忆T细胞的功能质量提供了有效的策略。
Memory CD8 T cells are a critical component of protective immunity and inducing effective memory T cell responses is a major goal of vaccines against chronic infections and tumors. Considerable effort has gone into designing vaccine regimens that will increase the magnitude of the memory response but there has been minimal emphasis on developing strategies to improve the functional qualities of memory T cells. In this study we show that mTOR, the mammalian target of rapamycin, is a major regulator of memory CD8 T cell differentiation and in contrast to what we expected the mTOR specific inhibitor rapamycin, an immunosuppressive drug, had surprising immunostimulatory effects on the generation of memory CD8 T cells. Treatment of mice with rapamycin following acute lymphocytic choriomeningitis virus (LCMV) infection enhanced not only the quantity but also the quality of virus specific CD8 T cells. Similar effects were seen after immunization of mice with a non-replicating VLP based vaccine. In addition, rapamycin treatment also enhanced memory T cell responses in non-human primates following vaccination with MVA (modified vaccinia virus - Ankara). Rapamycin was effective during both the expansion and contraction phases of the T cell response; during the expansion phase it increased the number of memory precursors and during the contraction phase (effector to memory transition) it accelerated the memory T cell differentiation program. Experiments using RNAi to inhibit mTOR, raptor or FKBP12 expression in antigen specific CD8 T cells showed that mTOR acts intrinsically through the mTORC1 pathway to regulate memory T cell differentiation. Thus, these studies identify a molecular pathway regulating memory formation and provide an effective strategy for improving the functional qualities of vaccine or infection induced memory T cells.
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影响因子：
30.5
作者：
通讯作者：
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影响因子：
30.5
作者：
Kaech, SM;Tan, JT;Ahmed, R
通讯作者：
Ahmed, R
影响因子：
30.5
作者：
通讯作者：
--
白介素（IL）-15和IL-7联合调节记忆表型CD8+细胞的体内稳态增殖，但对于记忆表型CD4+细胞不需要。
影响因子：
15.3
作者：
Tan, Joyce T;Ernst, Bettina;Kieper, William C;LeRoy, Eric;Sprent, Jonathan;Surh, Charles D
通讯作者：
Surh, Charles D
DOI：
10.1073/pnas.0800928105
发表时间：
2008-06-03
影响因子：
11.1
作者：
Sauer, Stephan;Bruno, Ludovica;Merkenschlager, Matthias
通讯作者：
Merkenschlager, Matthias