UNDERSTANDING AUTOREACTIVE T CELL PATHOGENICITY

了解自身反应性 T 细胞致病性

基本信息

批准号：
8835343
负责人：
Brian Todd Edelson
金额：
$ 38.13万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-05-05 至 2020-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8835343
关键词：
Autoantigens Autoimmune Diseases Autoimmunity Behavior CD28 gene CD4 Positive T Lymphocytes Cell physiology Cells Event Experimental Autoimmune Encephalomyelitis Gene Targeting Genes Genetic Transcription Goals Granulocyte-Macrophage Colony-Stimulating Factor Green Fluorescent Proteins Helper-Inducer T-Lymphocyte Immune Immune response Immunization Immunosuppressive Agents In Vitro Interferons Interleukin-1 Interleukin-10 Interleukin-17 Laboratories Mediating Modeling Molecular Multiple Sclerosis Mus Neuraxis Pathogenicity Play Population Process Production Proteins Receptor Signaling Regulation Regulator Genes Reporter Reporting Resistance Role Signal Transduction Supplementation System T-Lymphocyte Testing Transcription Coactivator Transcription Repressor/Corepressor Transcriptional Regulation Work autoreactive T cell base cell type cytokine insight mouse model neuroinflammation new therapeutic target prevent public health relevance research study response transcription factor

项目摘要

DESCRIPTION (provided by applicant): CD4 T helper (TH) cells drive autoimmunity through their production of proinflammatory cytokines. The molecular determinants controlling the cytokine production and pathogenicity of autoreactive T cells remain unclear. In experimental autoimmune encephalomyelitis (EAE), a mouse model of multiple sclerosis (MS), TH1, TH17 infiltrate the central nervous system (CNS). Remarkably, IFN-� and IL-17, the hallmark cytokines produced by TH1 and TH17 lineages, are not required for encephalitogenicity. Instead, the TH cell- cell-derived cytokine granulocyte-macrophage colony stimulating factor (GM-CSF, encoded by Csf2) plays a nonredundant role in mediating neuroinflammation. Immunosuppressive cytokines produced by autoreactive T cells, including IL-10, also influence T cell encephalitogenicity. We have discovered that mice deficient for the transcription factor Bhlhe40 are resistant to the induction of EAE. Bhlhe40-/- TH cells produce normal amounts of their hallmark cytokines, but produce decreased amounts of GM-CSF and increased amounts of IL-10. We will test the central hypothesis that Bhlhe40 is a required determinant for the pathogenicity of autoreactive T cells. In Aim 1, we will determine the mechanistic basis for Bhlhe40 function in neuroinflammation, testing the hypothesis that the nonencephalitogenicity of Bhlhe40-/- T cells is due to their cell-intrinsic IL-10 production. We will also test the hypothesi that Bhlhe40 acts as a direct transcriptional regulator of genes controlling autoreactive TH cell pathogenicity and determine the structural features of the Bhlhe40 protein required for this transcriptional regulation. In Aim 2, we will use Bhlhe40-green fluorescent protein (GFP) reporter mice to identify the signals that induce Bhlhe40 expression in T cells and test the hypothesis that Bhlhe40 expression determines the pathogenicity of autoreactive T cells. These studies will contribute to our understanding of how T cells acquire autoaggressive effector functions and could identify Bhlhe40 as a novel therapeutic target for the treatment of autoimmune disease.

描述（由申请人证明）：CD4 T助手（Th）细胞促进其促炎细胞因子，以控制自动反应性T细胞的细胞因子生产和病原体。 TH1，中枢神经系统（CNS）和Th17谱系，脑作用不需要。自动反应性的细胞因子告诉IL-10 d，缺乏THLHE40的小鼠具有抗EAE的诱导性，但是我们将测试BHLHE40的中心假设，但量减少了GM-CSF。在AIM 1 s中，BHLHE40在神经炎症中的功能中的自动反应性T-细胞的决定因素，测试了BHLHE40 - / - T细胞的非脑质量的假设。假设BHLHE40充当控制自动反应性H细胞病原体的基因的直接转录调节剂，并确定AIM 2中所需的BHLHE40蛋白的结构特征INTIFY THAT INDUHE40 EXPRESSION in T CELLS and TEST THE HYPOTHESIS THAT HLHE40 EXPRESSIS THE PATHOGENICTY OF AUTOREACTIVE T CELLS. THE STUDIES WILL CONTRIBUTE TO OUR UNDERSTANDING OF TELLS AUTOIRE AUTOIRE AUTOIRE GRESSIVE EFFECTOR Functions and Coulde Identify BHLHE40 AS AS AS AS AS AUTOIMMUNE DISEASEASEASEASEASEASEASESEASEASEASEASEASEASESE.