Role of RORgt+ (note: g: is gamma symbol) lymphocytes in Gut Tissue Homeostasis

项目概要/摘要： ILC 3、gdT 17和Th 17细胞具有共同的特征，例如，表达主转录因子RORgt 以及效应细胞因子IL-17 A、IL-17 F和IL-22，并且在不同的条件下执行不同的免疫功能。 环境背景。我们的初步数据表明，在Tfamfl/flRorc中，RORgt+ Tfam的细胞内源性缺失， cre小鼠影响RORgt+ gdT 17细胞和ILC 3s在体内的维持并导致小肠组织 通过簇状细胞-ILC 2回路进行重塑。线粒体控制免疫超越ATP的新概念 最近提出了一种新的方法。基于这个前提和我们的初步数据，我们假设， Tfam介导的线粒体呼吸在gdT 17细胞和ILC 3细胞中是gdT 17/ILC 3细胞的关键， 稳态和调节小肠组织重塑/代谢变化， 免疫/炎症。具体而言，我们将研究1）Tfam在gdT 17和ILC 3淋巴细胞中的作用 2）Tfam在gdT 17细胞和/或ILC 3中调节簇状细胞-ILC 2回路和小 肠组织重塑，和3）Tfam在gdT 17细胞和/或ILC 3中在调节微生物组中的作用， 小肠免疫和炎症。这些实验将提供一个机会来阐明Tfam- 在稳态下小肠中RORgt+淋巴细胞介导的线粒体呼吸， 在感染/免疫期间。我们的研究将提供新的细胞和分子见解的维护和 由Tfam调节的gdT 17细胞和ILC 3的功能。了解潜在的机制 Tfam对RORgt+细胞在调节小肠组织重塑和免疫中的需求可能 代表人类疾病治疗和/或预防的新范例。

Project Summary/Abstract: ILC3s, gdT17 and Th17 cells share common features, e.g., expressing the master transcription factor RORgt and the effector cytokines IL-17A, IL-17F and IL-22, and perform distinct immune functions under different environment context. Our preliminary data suggest that RORgt+ cell-intrinsic deletion of Tfam in Tfamfl/flRorc- cre mice affected RORgt+ gdT17 cells and ILC3s in vivo maintenance and led to small intestinal tissue remodeling via a tuft cell–ILC2 circuit. An emerging concept of mitochondrial control of immunity beyond ATP generation has recently been proposed. Based on the premise and our preliminary data, we hypothesize that that Tfam-mediated mitochondrial respiration in gdT17 cells and ILC3s is pivotal for gdT17/ILC3 cell homeostasis and regulation of small intestine tissue remodeling/metabolic changes and immunity/inflammation. Specifically, we will investigate 1) the role of Tfam in gdT17 and ILC3 lymphocyte maintenance, 2) the role of Tfam in gdT17 cells and/or ILC3s in regulating tuft cell-ILC2 circuit and small intestine tissue remodeling, and 3) the role of Tfam in gdT17 cells and/or ILC3s in regulation of microbiome and small intestinal immunity and inflammation. These experiments will offer an opportunity to elucidate Tfam- mediated mitochondrial respiration in RORgt+ lymphocytes in the small intestine under the steady state and during infection/immunity. Our study will provide novel cellular and molecular insights into the maintenance and function of gdT17 cells and ILC3s regulated by Tfam. Understanding the mechanisms underlying the requirement of Tfam for RORgt+ cells in regulation of small intestine tissue remodeling and immunity may represent a new paradigm for human disease treatment and/or prevention.