Cholesterol metabolites coordinate skin barrier immunity centered on innate dermal gammadelta T cells programmed to produce IL-17

摘要 免疫控制粘膜屏障的发展和维持是一个关键的过程，因为 免疫哨兵活动可导致皮肤、肺部和肠道炎症。位于粘膜组织的中央 动态平衡是产生3型细胞因子的淋巴细胞。细胞因子、细胞因子受体和主受体 参与组织发育和屏障防御的转录已经基于对 人和小鼠的功能丧失模型。然而，协调3型的非炎症性因子 组织中确保适当免疫反应和防止异常炎症的反应并不是很好。 特色化的。 我们发现，氧化甾醇是一种主要的胆固醇代谢产物，具有公认的免疫调节作用。 活动，是皮肤中被称为Tγδ17细胞的典型3型淋巴细胞的主要位置线索。 EBI2(由GPR183编码)是G蛋白偶联受体(GPCR)，它能感知特定类型的氧固醇， 并在所有产生3型细胞因子的淋巴细胞上表达。膳食胆固醇增加可提高Tgd17 皮肤界面的活动，通过增加氧固醇的产生和感觉。然而，组织驻留细胞如何 有助于生成皮肤固有分泌IL-17的最终位置线索的解剖框架 T淋巴细胞尚不清楚。此外，氧化甾醇是否参与了嗜皮性Tgd17的发生 而其他产生3型细胞因子的淋巴细胞尚不清楚。 在这个项目中，我们将测试Tgd17细胞通过感知线索来维持屏障组织动态平衡的假设 反映营养状态和来自周围神经系统的输入。上皮细胞的代谢变化- 通过GPR183在皮肤神经元壁龛中控制Tgd17的最佳显微解剖定位和功能。这 胆固醇代谢和神经元输入的综合感觉机制在Tγδ17早期被印记 胸腺细胞通过与一种新的胸腺上皮细胞亚群相互作用而成熟 氧类固醇。这个项目的概念基础是创新的，因为没有氧固醇的先例- 整合上皮-神经元-免疫通讯的受调控的粘膜组织中枢对屏障组织至关重要 健身。

Summary Immunological control of mucosal barrier development and maintenance is a critical process, as imbalances in immune sentinel activity can lead to skin, lung and gut inflammatory diseases. Central in the mucosal tissue homeostasis are type 3 cytokine producing lymphocytes. Cytokines, cytokines receptors and master transcriptions involved in tissue development and barrier fortification have been identified based on analyses of loss of function models in human and mice. However, non-inflammatory factors that orchestrate the type 3 responses in tissues to assure proper immune reactions and prevent aberrant inflammation have not been well characterized. We discovered that oxysterols, a major class of cholesterol metabolites with established immunomodulatory activities, are the primary positional cues for the stereotypical type 3 lymphocytes in the skin called Tγδ17 cells. Ebi2 (encoded by Gpr183) is the G protein coupled receptor (GPCR) that senses specific types of oxysterols, and is expressed on all type 3 cytokine producing lymphocytes. Increased dietary cholesterol enhances Tgd17 activity at the skin interface via augmented oxysterol production and sensing. However, how tissue resident cells contribute to the anatomical framework that generate the final positional cues for dermal IL-17 secreting innate T lymphocytes is not known. Moreover, whether oxysterols are involved in the development of skin-tropic Tgd17 and other type 3 cytokine producing lymphocytes is not known. In this project we will test the hypothesis that Tgd17 cells maintain barrier tissue homeostasis by sensing cues that reflect nutritional states and inputs from the peripheral nerve system. Metabolic changes in the epithelial- neuronal niche in the skin control optimal microanatomical Tgd17 positioning and function via GPR183. This integrated sensory mechanism for cholesterol metabolism and neuronal inputs is imprinted early in Tγδ17 thymocyte maturation through interactions with a novel subset of thymic epithelial cells programmed to produce oxysterols. The conceptual basis of this project is innovative as there are no precedents for the oxysterol- regulated mucosal tissue hub integrating epithelial-neuronal-immune communications critical for barrier tissue fitness.