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

基本信息

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
项目类别：
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

项目摘要

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，导致数百万人罹患它是由适应性和先天免疫失调引起的。特别是，Th17 细胞对于人类 MS 的发展和小鼠 EAE 的发展至关重要。自身免疫性神经炎症是多发性硬化症的主要病因之一，并制定治疗方法。 MS 研究的目标是了解 T 细胞和 Th17 细胞功能如何控制转化生长。 β因子 (TGF-β) 在 Th17 细胞分化和功能中发挥作用，但尚不清楚是否以及如何发挥作用。 TGF-β 以外的 TGF-β 超家族成员控制 MS/EAE 中的 Th17 细胞分化。我们最近的研究结果揭示了新的 TGF-β 超家族和调节 Th17 细胞的相关信号功能和自身免疫性神经炎症的发展：(1) SKI 蛋白，一种 TGF-β 信号传导抑制因子在 TGF-β 刺激下被降解，在体外和体内抑制 Th17 细胞分化， (2) T 细胞中的 SKI 表达完全保护小鼠免受 EAE，(3) Activin-A，TGF-β 超家族成员与 TGF-β 密切相关，在 EAE 期间以及发炎组织中的活化 T 细胞和促炎细胞因子的存在，以及 (4) Activin-A+IL6 诱导 SKI 降解和表型类似于致病性而非非致病性 Th17 细胞的 Th17 细胞分化为因此，我们认为 TGF-β 超家族成员 Activin-A 是一种独特的新因子。 TGF-β 通过 SKI 促进致病性 Th17 功能和自身免疫性神经炎症。研究中，我们建议实现以下三个目标 1：解决 Th17 是否需要 Activin-A。细胞功能和 EAE 目标 2：揭示 Activin-A 诱导 Th17 细胞生成和的分子程序。功能；目标 3：研究 SKI 控制 Th17 细胞功能和 EAE 的机制。了解 Th17 细胞在自身免疫过程中如何发挥作用存在巨大但尚未满足的需求这项研究旨在揭示以前未被认识的细胞和分子机制。 TGF-β 超家族信号传导在控制 Th17 细胞分化和自身免疫功能中的作用。这项研究的成功将为 T 细胞介导的自身免疫获得重要的机制见解神经炎症，并为如何通过靶向 TGF-β 超家族减轻相关疾病提供新的思路信号通路。