Frumento Guido, Verma Kriti, Croft Wayne, White Andrea, Zuo Jianmin, Nagy Zsuzsanna, Kissane Stephen, Anderson Graham, Moss Paul, Chen Frederick E
Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, UK; NHS Blood and Transplant, Birmingham, UK.
Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, UK.
iScience. 2020 Apr 24;23(4):100989. doi: 10.1016/j.isci.2020.100989. Epub 2020 Mar 19.
Primary stimulation of T cells is believed to trigger unidirectional differentiation from naive to effector and memory subsets. Here we demonstrate that IL-7 can drive the phenotypic reversion of recently differentiated human central and effector memory CD8 T cells into a naive-like phenotype. These "naive-revertant" cells display a phenotype similar to that of previously reported stem cell memory populations and undergo rapid differentiation and functional response following secondary challenge. The chromatin landscape of reverted cells undergoes substantial epigenetic reorganization with increased accessibility for cytokine-induced mediators such as STAT and closure of BATF-dependent sites that drive terminal differentiation. Phenotypic reversion may at least partly explain the generation of "stem cell memory" CD8 T cells and reveals cells within the phenotypically naive CD8 T cell pool that are epigenetically primed for secondary stimulation. This information provides insight into mechanisms that support maintenance of T cell memory and may guide therapeutic manipulation of T cell differentiation.
T细胞的初次刺激被认为会引发从幼稚细胞向效应细胞和记忆亚群的单向分化。在此，我们证明白细胞介素-7（IL-7）可驱动最近分化的人类中枢和效应记忆CD8 T细胞向幼稚样表型的表型逆转。这些“幼稚逆转”细胞表现出与先前报道的干细胞记忆群体相似的表型，并在再次刺激后经历快速分化和功能反应。逆转细胞的染色质景观经历了实质性的表观遗传重组，细胞因子诱导的介质（如STAT）的可及性增加，驱动终末分化的BATF依赖位点关闭。表型逆转可能至少部分解释了“干细胞记忆”CD8 T细胞的产生，并揭示了表型幼稚的CD8 T细胞库中那些在表观遗传上为二次刺激做好准备的细胞。这些信息为支持T细胞记忆维持的机制提供了见解，并可能指导T细胞分化的治疗性操作。
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