Division of Biological Sciences, Molecular Biology Section, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0377, USA; Department of Cellular and Molecular Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0377, USA.
Department of Cellular and Molecular Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0377, USA.
Cell Rep. 2021 Jan 26;34(4):108674. doi: 10.1016/j.celrep.2020.108674.
Naive and memory T cells are maintained in a quiescent state, yet capable of rapid response and differentiation to antigen challenge via molecular mechanisms that are not fully understood. In naive cells, the deletion of Foxo1 following thymic development results in the increased expression of multiple AP-1 family members, rendering T cells less able to respond to antigenic challenge. Similarly, in the absence of FOXO1, post-infection memory T cells exhibit the characteristics of extended activation and senescence. Age-based analysis of human peripheral T cells reveals that levels of FOXO1 and its downstream target, TCF7, are inversely related to host age, whereas the opposite is found for AP-1 factors. These characteristics of aging also correlate with the formation of T cells manifesting features of cellular senescence. Our work illustrates a role for FOXO1 in the active maintenance of stem-like properties in T cells at the timescales of acute infection and organismal life span.
幼稚 T 细胞和记忆 T 细胞处于静止状态，但通过分子机制能够迅速对抗原挑战做出反应和分化，这些分子机制尚未完全阐明。在幼稚细胞中，胸腺发育后 Foxo1 的缺失导致多个 AP-1 家族成员的表达增加，使 T 细胞对抗原挑战的反应能力降低。同样，在没有 FOXO1 的情况下，感染后记忆 T 细胞表现出延长激活和衰老的特征。对人类外周 T 细胞的年龄分析表明，FOXO1 及其下游靶标 TCF7 的水平与宿主年龄呈负相关，而 AP-1 因子则相反。这些衰老特征也与表现出细胞衰老特征的 T 细胞的形成相关。我们的工作说明了 FOXO1 在急性感染和机体寿命的时间尺度上，在 T 细胞中维持干细胞样特性的活跃作用。
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