Epithelial HVEM maintains intraepithelial T cell survival and contributes to host protection.
Epithelial HVEM maintains intraepithelial T cell survival and contributes to host protection.
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上皮HVEM维持上皮内T细胞存活并有助于宿主保护。
DOI：
10.1126/sciimmunol.abm6931
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发表时间：
2022-07-29
影响因子：
24.8
通讯作者：
Kronenberg, Mitchell
中科院分区：
文献类型：
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作者：
Seo, Goo-Young;Takahashi, Daisuke;Wang, Qingyang;Mikulski, Zbigniew;Chen, Angeline;Chou, Ting-Fang;Marcovecchio, Paola;McArdle, Sara;Sethi, Ashu;Shui, Jr-Wen;Takahashi, Masumi;Surh, Charles D;Cheroutre, Hilde;Kronenberg, Mitchell
上皮内 T 细胞 (IET) 与肠上皮细胞和下面的基底膜密切接触，它们检测侵入性病原体。在稳定状态或感染后，肠上皮细胞和基底膜如何影响 IET 的存活和功能尚不清楚。疱疹病毒进入介质 (HVEM) 是 TNF 受体超家族的成员，由肠上皮细胞组成型表达，对于保护免受病原菌的侵害非常重要。在这里，我们表明，在稳态 LIGHT 下，HVEM 配体与上皮 HVEM 结合可促进小肠 IET 的存活。 RNA-seq 和在上皮类器官中添加 HVEM 配体表明，HVEM 增加了基底膜蛋白的上皮合成，包括与 IET 表达的 β1 整合素结合的 IV 型胶原蛋白。因此，我们提出 IET 的存活取决于 β1 整合素与 IV 型胶原蛋白的结合，并且表明 β1 整合素与 IV 型胶原蛋白的相互作用支持 IET 的体外存活。此外，T 淋巴细胞缺乏 β1 整合素表达会降低体内 TCR αβ+ IET。活体显微镜显示，在没有上皮 HVEM 的情况下，IET 的巡逻运动减少。作为数量和运动减少的可能后果，缺乏上皮 HVEM、HVEM 配体或 β1 整合素的小鼠对肠道沙门氏菌的保护性反应降低。因此，组织驻留 IET 在稳态和感染后依赖于上皮细胞表达的 HVEM 来合成 IV 型胶原。 IV 型胶原蛋白与 IET 上的 β1 整合素结合，这对于 IET 的维持以及最终 IET 在粘膜免疫中的保护功能非常重要。上皮 HVEM 维持上皮内 T 细胞的存活和功能并支持宿主防御。
Intraepithelial T cells (IETs) are in close contact with intestinal epithelial cells and the underlying basement membrane, and they detect invasive pathogens. How intestinal epithelial cells and basement membrane influence IETs survival and function, at steady state or following infection, is unclear. The herpes virus entry mediator (HVEM), a member of the TNF receptor superfamily, is constitutively expressed by intestinal epithelial cells and is important for protection from pathogenic bacteria. Here, we showed that at steady-state LIGHT, an HVEM ligand, binding to epithelial HVEM promoted the survival of small intestine IETs. RNA-seq and addition of HVEM ligands to epithelial organoids indicated that HVEM increased epithelial synthesis of basement membrane proteins, including collagen IV, which bound to β1 integrins expressed by IETs. Therefore, we proposed IETs survival depended on β1 integrin binding to collagen IV, and showed β1 integrin-collagen IV interactions supported IETs survival in vitro. Moreover, the absence of β1 integrin expression by T lymphocytes decreased TCR αβ+ IETs in vivo. Intravital microscopy showed that the patrolling movement of IETs was reduced without epithelial HVEM. As likely consequences of decreased number and movement, protective responses to Salmonella enterica were reduced in mice lacking either epithelial HVEM, HVEM ligands, or β1 integrins. Therefore, tissue-resident IETs, at steady state and following infection, depended on HVEM expressed by epithelial cells for the synthesis of collagen IV by epithelial cells. Collagen IV engaged β1 integrins on IETs that were important for their maintenance and ultimately for the protective function of IETs in mucosal immunity. Epithelial HVEM maintains intraepithelial T cell survival and function and supports host defense.