Differentiation of CD8 memory T cells depends on Foxo1.
Differentiation of CD8 memory T cells depends on Foxo1.
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DOI：
10.1084/jem.20130392
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发表时间：
2013-06-03
期刊：
影响因子：
--
通讯作者：
Hedrick SM
中科院分区：
文献类型：
--
作者：
Hess Michelini R;Doedens AL;Goldrath AW;Hedrick SM
转录因子Foxo 1是记忆性CD 8 + T细胞分化所必需的，它的缺失阻碍了继发性感染的清除。叉头O转录因子（FOXO）整合了一系列细胞外信号，包括生长因子信号传导、炎症、氧化应激和营养可用性，以实质性地改变基因表达程序并调节细胞存活、细胞周期进程和许多尚未阐明的细胞类型特异性反应。初始抗原特异性CD 8 + T细胞在病原体暴露的数天内经历快速扩增和效应子功能的武装。此外，在扩增的高峰期，它们形成能够自我更新和无限期存活的记忆T细胞的前体。使用淋巴细胞性脉络丛脑膜炎病毒Armstrong来探测对感染的反应，我们发现Foxo 1 −/− CD 8 + T细胞正常扩增，效应分化没有缺陷，但在抗原清除后很长时间内继续表现出效应T细胞的特征。通常富含记忆前体细胞的KLRG 1 lo CD 8 + T细胞保留颗粒酶B和CD 69表达，并且不能上调TCF 7、EOMES和其他记忆特征基因。作为一种相关性，Foxo 1 −/− CD 8 + T细胞在二次感染后几乎无法扩增。总的来说，这些结果证明了FOXO 1在建立后效应记忆程序中的内在作用，该程序对于形成能够免疫再激活的长寿记忆细胞至关重要。
The transcription factor Foxo1 is required for the differentiation of memory CD8+ T cells, and its absence hinders clearance of secondary infections. The forkhead O transcription factors (FOXO) integrate a range of extracellular signals, including growth factor signaling, inflammation, oxidative stress, and nutrient availability, to substantially alter the program of gene expression and modulate cell survival, cell cycle progression, and many yet to be unraveled cell type–specific responses. Naive antigen-specific CD8+ T cells undergo a rapid expansion and arming of effector function within days of pathogen exposure. In addition, by the peak of expansion, they form precursors to memory T cells capable of self-renewal and indefinite survival. Using lymphocytic choriomeningitis virus Armstrong to probe the response to infection, we found that Foxo1−/− CD8+ T cells expand normally with no defects in effector differentiation, but continue to exhibit characteristics of effector T cells long after antigen clearance. The KLRG1lo CD8+ T cells that are normally enriched for memory-precursor cells retain Granzyme B and CD69 expression, and fail to up-regulate TCF7, EOMES, and other memory signature genes. As a correlate, Foxo1−/− CD8+ T cells were virtually unable to expand upon secondary infection. Collectively, these results demonstrate an intrinsic role for FOXO1 in establishing the post-effector memory program that is essential to forming long-lived memory cells capable of immune reactivation.
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