Tsc1 promotes the differentiation of memory CD8+ T cells via orchestrating the transcriptional and metabolic programs
Tsc1 promotes the differentiation of memory CD8+ T cells via orchestrating the transcriptional and metabolic programs
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DOI：
10.1073/pnas.1404264111
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发表时间：
2014-10-14
影响因子：
11.1
通讯作者：
Chi, Hongbo
中科院分区：
文献类型：
--
作者：
Shrestha, Sharad;Yang, Kai;Chi, Hongbo
记忆CD8(+) T细胞是保护性免疫的重要组成部分。通过雷帕霉素 (mTOR) 机制靶标的信号传导涉及效应 T 细胞和记忆 T 细胞分化的调节。然而，人们对控制 mTOR 活性的机制或 mTOR 调节的效应通路了解甚少。我们在这里描述了结节性硬化症1（Tsc1），mTOR信号传导的调节剂，在促进记忆CD8（+）T细胞响应单核细胞增生李斯特菌感染的分化和功能中发挥着至关重要的作用。在经历过抗原的CD8+T细胞中特异性删除Tsc1的小鼠会诱发正常的效应反应，但记忆T细胞的生成以及它们以细胞固有的方式对抗原再次暴露的回忆反应明显受损。 Tsc1 缺陷抑制了记忆前体效应细胞的生成，同时促进了短期效应细胞的分化。转录组分析表明，Tsc1 协调免疫功能、转录调控和细胞代谢的基因表达程序。此外，Tsc1 缺失导致 mTORC1 活性过高，并导致糖酵解和氧化代谢失调，以响应 IL-15 刺激。这些发现建立了一个 Tsc1 介导的检查点，将免疫信号和细胞代谢联系起来，协调记忆 CD8(+) T 细胞的发育和功能。
Memory CD8(+) T cells are an essential component of protective immunity. Signaling via mechanistic target of rapamycin (mTOR) has been implicated in the regulation of the differentiation of effector and memory T cells. However, little is understood about the mechanisms that control mTOR activity, or the effector pathways regulated by mTOR. We describe here that tuberous sclerosis 1 (Tsc1), a regulator of mTOR signaling, plays a crucial role in promoting the differentiation and function of memory CD8(+) T cells in response to Listeria monocytogenes infection. Mice with specific deletion of Tsc1 in antigen-experienced CD8(+) T cells evoked normal effector responses, but were markedly impaired in the generation of memory T cells and their recall responses to antigen reexposure in a cell-intrinsic manner. Tsc1 deficiency suppressed the generation of memory-precursor effector cells while promoting short-lived effector cell differentiation. Transcriptome analysis indicated that Tsc1 coordinated gene expression programs underlying immune function, transcriptional regulation, and cell metabolism. Furthermore, Tsc1 deletion led to excessive mTORC1 activity and dysregulated glycolytic and oxidative metabolism in response to IL-15 stimulation. These findings establish a Tsc1-mediated checkpoint in linking immune signaling and cell metabolism to orchestrate memory CD8(+) T-cell development and function.