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: 10539286
• 负责人: Yisong Wan
• 金额: $ 38.3万
• 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/10539286
• 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; IL17 gene; IL6 gene; Immune; Immune Tolerance; In Vitro; Inflammatory; Interleukin-10; 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-Cell Activation; T-Lymphocyte; TGF-beta type I receptor; Tissues; Transforming Growth Factor beta; 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.

项目总结： 多发性硬化症(MS)是一种衰弱的自身免疫性神经炎性疾病，导致数百万人 世界各地的人们。它是由适应性免疫和先天免疫失调引起的。CD4T细胞起到关键作用 对人类多发性硬化症的发展和小鼠的EAE发展。特别是，Th17细胞是 自身免疫性神经炎。了解多发性硬化症的病因和开发治疗方法 多发性硬化症研究的目标是了解T细胞和Th17细胞的功能是如何控制的。转型增长 转化生长因子-β(Fel-β)在Th17细胞分化和功能中起重要作用。然而，目前还不清楚是否以及如何 转化生长因子-β超家族成员而不是转化生长因子-β调控MS/EAE中Th17细胞的分化。 我们最近的发现揭示了新的转化生长因子-β超家族及其相关信号调节Th17细胞 自身免疫性神经炎的功能与发展：(1)转化生长因子-β信号转导因子SKI蛋白 在转化生长因子-β刺激下降解的抑制因子，在体外和体内抑制Th17细胞的分化， (2)T细胞中SKI的表达可完全保护小鼠免受EAE的影响；(3)转化生长因子-β超家族成员激活素-A 这与转化生长因子-β密切相关，在EAE过程中上调，在炎症组织中活化的T细胞和在 促炎症细胞因子的存在，以及(4)激活素-A+IL-6诱导的SKI降解和 表型类似致病(而非非致病)的Th17细胞分化为 推广EAE。因此，我们假设转化生长因子-β超家族成员激活素-A是一种独特的新因子 转化生长因子-β通过SKI促进致病Th1 7功能和自身免疫性神经炎症。在这 通过研究，我们提出要达到以下三个目标。目标1：解决Th17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Th17细胞生成的分子程序 目的：探讨SKI调控Th17细胞功能和EAE的机制。 在理解Th17细胞如何在自身免疫中发挥作用方面，有一个巨大而尚未得到满足的需求 神经炎。这项研究旨在揭示以前未被认识的细胞和分子机制。 潜在转化生长因子-β超家族信号在控制Th17细胞分化和自身免疫功能中的作用。 这项研究的成功将获得对T细胞介导的自身免疫的关键机制的洞察 神经炎症和如何通过靶向转化生长因子-β超家族来减轻相关疾病 信号通路。