Molecular Biology Section, Division of Biological Sciences, Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA, USA.
J Exp Med. 2013 Jun 3;210(6):1189-200. doi: 10.1084/jem.20130392. Epub 2013 May 27.
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 KLRG1(lo) 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.
叉头框 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、炎症、氧化应激和营养可用性，从而显著改变基因表达程序，并调节细胞存活、细胞周期进程以及许多尚未阐明的细胞类型特异性反应。幼稚抗原特异性 CD8(+)T 细胞在病原体暴露后的几天内经历快速扩增和效应功能的武装。此外，在扩增的高峰期，它们形成能够自我更新和无限存活的记忆 T 细胞前体。我们使用淋巴细胞性脉络丛脑膜炎病毒 Armstrong 来探究对感染的反应，发现 Foxo1(-/-)CD8(+)T 细胞正常扩增，没有效应分化缺陷，但在抗原清除后很长时间仍表现出效应 T 细胞的特征。正常富含记忆前体细胞的 KLRG1(lo)CD8(+)T 细胞保留颗粒酶 B 和 CD69 的表达，并且不能上调 TCF7、EOMES 和其他记忆特征基因。作为相关结果，Foxo1(-/-)CD8(+)T 细胞几乎无法在二次感染时扩增。总之，这些结果表明 FOXO1 在建立后效应记忆程序中具有内在作用，这对于形成能够免疫激活的长寿记忆细胞至关重要。
