RIG-I在肠道TRM样细胞形成、维持及肠道免疫防御中的作用和机制研究

The TCRb+CD8+CD103+ T cells in the intestinal epithelial layer show a resident memory T (TRM) cell-like phenotype and have an important role in host defense against microbial infection, however, the mechanism for the formation and homeostasis of these TRM-like cells is unclear. RIG-I is an intracellular antiviral innate immune receptors and plays an essential role in antiviral innate immunity by triggering type 1 interferon production through MAVS-mediated signaling pathway. Our preliminary results showed that the RIG-I KO mice had impaired host defense against Citrobacter when infected via intragastric administration. In contrast, RIG-I KO mice showed comparable hose defense to this bacteria when infected via intraperitoneal injection. Further experiments showed that the TRM-like cells in the intestinal epithelial layer were lost in RIG-I KO mice, suggesting that RIG-I might promote host defense against bacteria via maintaining TRM-like cells in the intestine. In addition, we found that the role of RIG-I in host defense and homeostasis of TRM-like cells was independent of MAVS signaling. Based on these preliminary results, we planned to study the MAVS-independent role and mechanism of RIG-I in the development, differentiation, and homeostasis of TRM-like cells and host defense in intestine. This will be helpful to understand the mechanism for the formation of special immune status in the intestine and also the MAVS-independent role of RIG-I in immunity.

肠道上皮内存在大量TCRb+CD8+CD103+具有组织驻留记忆表型特征的上皮内淋巴细胞（TRM样细胞），有助于快速清除病原微生物感染。但是TRM样细胞形成和维持机制并不清楚。RIG-I作为一种胞内抗病毒固有免疫受体，能通过下游接头蛋白MAVS诱导I型干扰素产生从而发挥抗病毒功能。我们初步实验结果表明RIG-I缺陷小鼠抵抗肠道细菌感染能力显著下降，但对腹腔感染抵抗能力无显著区别。进一步结果发现RIG-I缺陷小鼠中肠道TRM样细胞显著减少，提示RIG-I可通过调控TRM样细胞稳态发挥免疫防御作用。此外，RIG-I在肠道免疫防御和TRM样细胞维持中的作用不依赖MAVS。以此为基础，本课题将系统研究RIG-I在肠道TRM样细胞发育分化或者稳态维持及其在肠道免疫防御中的非MAVS依赖的作用及细胞和分子机制。本课题有助于了解肠道区域免疫特性形成机制和RIG-I独立于MAVS的免疫生物学功能。

肠道上皮内存在大量TCRb+CD8+CD103+具有组织驻留记忆表型特征的上皮内淋巴细胞（TRM 样细胞），有助于快速清除病原微生物感染。但是TRM样细胞形成和维持机制并不清楚。RIG-I 作为一种胞内抗病毒固有免疫受体，能通过下游接头蛋白MAVS诱导I型干扰素产生从而发挥抗病毒功能。本项目系统探究RIG-I在肠道TRM样细胞发育分化或者稳态维持及其在肠道免疫防御中的作用及细胞和分子机制。研究结果显示肠道共生病毒在 IELs 稳态维持中起着非常关键的作用。清除肠道共生病毒后，肠道 IELs 细胞总数明显减少，但并不影响其他脏器的淋巴细胞数量。进一步研究发现清除肠道共生病毒主要导致 CD8αα+ TCRβ+ IELs 细胞和 CD8αβ+ TCRβ+ IELs 细胞显著减少，但对 TCRγδ+和 CD4+ TCRαβ+细胞无显著影响。随后，我们发现肠道共生病毒通过 RIG-I-MAVS 信号通路维持 IELs 细胞稳态。进一步的机制研究表明，肠道共生病毒和 RIG-I-MAVS 信号通路对 IELs 调控作用不依赖其下游 I 型干扰素，而依赖于 IL-15 产生。最后，我们发现清除肠道驻留病毒或 MAVS 缺失后，DSS 诱导的肠炎明显加重，而回补 IL-15 可以有效恢复 IELs 细胞数量并显著减轻肠炎症状。该项研究表明肠道共生病毒能够被肠道抗原呈递细胞上的 RIG-I 识别并通过其下游非经典的 MAVS-IRF1-IL-15 信号通路维持肠道 IELs 细胞稳态。本课题有助于了解肠道区域免疫特性形成机制，为相关疾病的治疗提供潜在的干预手段。