La Jolla Institute for Immunology, La Jolla, CA, USA.
Institute for Basic Science (IBS), Academy of Immunology and Microbiology, Pohang, South Korea.
Sci Immunol. 2022 Jul 29;7(73):eabm6931. doi: 10.1126/sciimmunol.abm6931.
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 IET survival and function, at steady state or after 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 β integrins expressed by IETs. Therefore, we proposed that IET survival depended on β integrin binding to collagen IV and showed that β integrin-collagen IV interactions supported IET survival in vitro. Moreover, the absence of β 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 were reduced in mice lacking either epithelial HVEM, HVEM ligands, or β integrins. Therefore, IETs, at steady state and after infection, depended on HVEM expressed by epithelial cells for the synthesis of collagen IV by epithelial cells. Collagen IV engaged β integrins on IETs that were important for their maintenance and for their protective function in mucosal immunity.
上皮内 T 细胞（IETs）与肠上皮细胞和基底膜紧密接触，并检测入侵病原体。在稳态或感染后，肠上皮细胞和基底膜如何影响 IET 的存活和功能尚不清楚。疱疹病毒进入介体（HVEM）是 TNF 受体超家族的成员，它在肠上皮细胞中持续表达，对于保护免受致病细菌的侵害非常重要。在这里，我们表明在稳态下，HVEM 配体 LIGHT 与上皮 HVEM 的结合促进了小肠 IET 的存活。RNA-seq 和向上皮类器官中添加 HVEM 配体表明，HVEM 增加了上皮细胞合成基底膜蛋白，包括 IET 表达的β整合素结合的 IV 型胶原。因此，我们提出 IET 的存活取决于β整合素与 IV 型胶原的结合，并表明β整合素-胶原 IV 相互作用支持 IET 在体外的存活。此外，T 淋巴细胞中缺乏β整合素表达会减少体内 TCR αβ IET。体内显微镜观察显示，上皮细胞 HVEM 缺失会减少 IET 的巡逻运动。由于数量和运动减少的可能后果，缺乏上皮细胞 HVEM、HVEM 配体或β整合素的小鼠对 的保护反应减少。因此，在稳态和感染后，IET 依赖于上皮细胞表达的 HVEM 来合成上皮细胞的 IV 型胶原。IV 型胶原与 IET 上的β整合素结合，对其维持和粘膜免疫中的保护功能非常重要。
