Hypoxia acts as an environmental cue for the human tissue-resident memory T cell differentiation program
Hypoxia acts as an environmental cue for the human tissue-resident memory T cell differentiation program
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DOI：
10.1172/jci.insight.138970
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发表时间：
2021-05-24
期刊：
影响因子：
8
通讯作者：
Yee, Cassian
中科院分区：
文献类型：
--
作者：
Hasan, Farah;Chiu, Yulun;Yee, Cassian
组织驻留记忆T细胞（T-RM）提供对抗感染性疾病的前线防御并有助于抗肿瘤免疫;然而，除了TGF-β的必要性之外，关于T-RM诱导线索的知识仍然不完整，特别是对于人类细胞。氧张力是区分外周组织和循环系统的一个环境线索，在这里，我们证明了在缺氧和TGF-β 1存在的情况下，人类CD 8（+）T细胞的分化导致了T-RM表型的发展，其特征在于表达人T-RM标志的CD 69（+）CD 103（+）细胞增加超过5倍，并富集内源性人T-RM标志。RM基因特征，包括粘附分子表达增加和再循环相关基因表达减少。缺氧和TGF-β（1）协同作用产生的T-RM表型细胞数量明显多于单独的任一种条件，对来自单独和组合条件的这些细胞的比较显示出不同的表型和转录谱，表明对环境的编程反应而不仅仅是扩增。我们的研究结果确定了一个可能以前未报告的线索T-RM分化程序，并可以使人T-RM表型细胞在体外的基础研究和翻译应用，如过继细胞治疗的容易产生。
Tissue-resident memory T cells (T-RM) provide frontline defense against infectious diseases and contribute to antitumor immunity; however, aside from the necessity of TGF-beta, knowledge regarding T-RM-inductive cues remains incomplete, particularly for human cells. Oxygen tension is an environmental cue that distinguishes peripheral tissues from the circulation, and here, we demonstrate that differentiation of human CD8(+) T cells in the presence of hypoxia and TGF-beta(1) led to the development of a T-RM phenotype, characterized by a greater than 5-fold increase in CD69(+)CD103(+) cells expressing human T-RM hallmarks and enrichment for endogenous human T-RM gene signatures, including increased adhesion molecule expression and decreased expression of genes involved in recirculation. Hypoxia and TGF-beta(1) synergized to produce a significantly larger population of T-RM phenotype cells than either condition alone, and comparison of these cells from the individual and combination conditions revealed distinct phenotypic and transcriptional profiles, indicating a programming response to milieu rather than a mere expansion. Our findings identify a likely previously unreported cue for the T-RM differentiation program and can enable facile generation of human T-RM phenotype cells in vitro for basic studies and translational applications such as adoptive cellular therapy.