TGF-b superfamily signaling in controlling Th17 cell function in autoimmune neuroinflammation

TGF-b 超家族信号传导在控制自身免疫性神经炎症中 Th17 细胞功能

• 批准号: 10330037
• 负责人: Yisong Wan
• 金额: $ 38.32万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-01-16 至 2025-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10330037
• 关键词: Address; Adopted; Autoimmune; Autoimmunity; CD4 Positive T Lymphocytes; Cell Differentiation process; Cell physiology; Cells; Critical Pathways; Development; Disease; Etiology; Experimental Autoimmune Encephalomyelitis; Generations; Genes; Genetic; Goals; Granulocyte-Macrophage Colony-Stimulating Factor; Homeostasis; Human; IL6 gene; Immune; In Vitro; Interleukin-10; Interleukin-17; Light; Mediating; Molecular; Molecular Target; Multiple Sclerosis; Mus; Natural Immunity; Pathogenicity; Pathology; Pathway interactions; Persons; Phenotype; Proteins; Regulator Genes; Research; Role; SKI gene; Signal Pathway; Signal Transduction; T-Lymphocyte; TGF-beta type I receptor; Tissues; Transforming Growth Factor beta; Transforming Growth Factors; activin A; adaptive immunity; cytokine; effective therapy; genetic signature; in vivo; insight; interest; member; multiple sclerosis treatment; neuroinflammation; novel; programs; receptor; success

Project Summary: Multiple sclerosis (MS) is a debilitating autoimmune neuroinflammation disease inflicting millions of people worldwide. It is caused by dysregulated adaptive and innate immunity. CD4 T cells critically contribute to MS development in humans and EAE development in mice. Particularly, Th17 cells are central to autoimmune neuroinflammation. To understand the etiology of and develop treatment for MS, one of the main goals of MS research is to understand how T cell and Th17 cell function are controlled. Transforming growth factor–β (TGF-β) is instrumental in Th17 cell differentiation and function. Yet it is unclear whether and how TGF-β superfamily member other than TGF-β controls Th17 cell differentiation in MS/EAE. Our recent findings revealed novel TGF-β superfamily and related signaling to regulate Th17 cell function and the development of autoimmune neuroinflammation: (1) SKI protein, a TGF-β signaling suppressor that is degraded upon TGF-β stimulation, suppresses Th17 cell differentiation in vitro and in vivo, (2) SKI expression in T cells completely protected mice from EAE, (3) Activin-A, a TGF-β superfamily member that is closely related to TGF-β, was upregulated during EAE and in activated T cells in inflamed tissues and in the presence of proinflammatory cytokines, and (4) Activin-A+IL6 induced SKI degradation and the differentiation of Th17 cells that phenotypically resemble pathogenic- rather than non-pathogenic-Th17 cells to promote EAE. We therefore hypothesize that TGF-β superfamily member Activin-A is a novel factor distinct from TGF-β to promote pathogenic Th17 function and autoimmune neuroinflammation through SKI. In this study, we proposed to reach the following three Aims. AIM 1: Address whether Activin-A is required for Th17 cell function and EAE. AIM 2: Reveal the molecular program of Activin-A induced Th17 cell generation and function; AIM 3: Investigate the mechanisms underlying SKI controlled Th17 cell function and EAE. There is a great and yet unmet need in the understanding of how Th17 cell function during autoimmune neuroinflammation. This study aims to reveal previous unappreciated cellular and molecular mechanisms underlying TGF-β superfamily signaling in controlling Th17 cell differentiation and function for autoimmunity. The success of this study will gain critical mechanistic insights into T cell mediated autoimmune neuroinflammation and shed new light on how to mitigate related disease by targeting TGF-β superfamily signaling pathways.

项目概要： 多发性硬化症（MS）是一种使人衰弱的自身免疫性神经炎症疾病， 世界各地的人们。它是由失调的适应性和先天免疫引起的。CD 4 T细胞对免疫系统的影响 与人类MS发展和小鼠EAE发展有关。特别是，Th 17细胞是 自身免疫性神经炎症了解MS的病因并制定治疗方法， MS研究的目的是了解T细胞和Th 17细胞功能是如何控制的。转化生长 因子-β（TGF-β）在Th 17细胞分化和功能中起作用。然而，目前还不清楚是否以及如何 TGF-β超家族成员控制MS/EAE中的Th 17细胞分化。 我们最近的发现揭示了新的TGF-β超家族和相关信号转导对Th 17细胞的调节作用 功能和自身免疫性神经炎症的发展：（1）SKI蛋白，一种TGF-β信号通路 在TGF-β刺激下降解的抑制因子，在体外和体内抑制Th 17细胞分化， (2)SKI在T细胞中的表达完全保护小鼠免受EAE的侵害。（3）活化素A，TGF-β超家族成员 与TGF-β密切相关，在EAE期间和炎症组织中的活化T细胞中上调， 促炎细胞因子的存在，和（4）激活素-A + IL 6诱导的SKI降解， 表型上类似于致病性而非致病性Th 17细胞的Th 17细胞的分化， 促进EAE。因此，我们假设TGF-β超家族成员激活素A是一种新的因子， 从TGF-β通过SKI促进致病性Th 17功能和自身免疫性神经炎症。在这 在这项研究中，我们提出了以下三个目标。目的1：解决Th 17是否需要激活素A 细胞功能和EAE。目的2：揭示激活素A诱导Th 17细胞生成的分子程序， 目的3：研究SKI对Th 17细胞功能和EAE的调控机制。 有一个伟大的，但尚未满足的需要，在了解如何Th 17细胞的功能，在自身免疫性 神经炎症本研究旨在揭示以前未被重视的细胞和分子机制 在控制Th 17细胞分化和自身免疫功能中潜在的TGF-β超家族信号传导。 这项研究的成功将为T细胞介导的自身免疫性疾病提供重要的机制见解。 神经炎症，并阐明如何通过靶向TGF-β超家族减轻相关疾病 信号通路