UNDERSTANDING AUTOREACTIVE T CELL PATHOGENICITY

了解自身反应性 T 细胞致病性

• 批准号: 9247751
• 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
• 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/9247751
• 关键词: Abnormal Cell; Alpha Cell; Autoantigens; Autoimmune Diseases; Autoimmunity; Behavior; CD28 gene; CD4 Positive T Lymphocytes; Cell physiology; Cells; Event; Experimental Autoimmune Encephalomyelitis; Gene Expression Regulation; 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; autoreactivity; cell type; cytokine; experimental study; inducible gene expression; insight; interleukin-10 receptor; mouse model; neuroinflammation; new therapeutic target; prevent; public health relevance; response; transcription factor

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(由申请人提供)：CD4T辅助(TH)细胞通过产生促炎细胞因子来驱动自身免疫。控制细胞因子产生和自身反应性T细胞致病性的分子决定因素仍不清楚。在实验性自身免疫性脑脊髓炎(EAE)中，多发性硬化症(MS)的小鼠模型中，TH1、TH17侵袭中枢神经系统(CNS)。值得注意的是，由Th1和Th17谱系产生的标志性细胞因子干扰素-�和IL-17不是脑炎发生所必需的。相反，TH细胞衍生的细胞因子粒细胞-巨噬细胞集落刺激因子(GM-CSF，由CSF2编码)在介导神经炎症方面发挥着非多余的作用。自身反应性T细胞产生的免疫抑制细胞因子，包括IL-10，也影响T细胞的脑原性。我们发现，缺乏转录因子Bhlhe40的小鼠对EAE的诱导具有抵抗力。Bhlhe40-/-TH细胞产生正常数量的标志性细胞因子，但产生数量减少的GM-CSF和增加数量的IL-10。我们将检验核心假设，即Bhlhe40是自身反应性T细胞致病所必需的决定因素。在目标1中，我们将确定Bhlhe40在神经炎症中作用的机制基础，验证Bhlhe40-/-T细胞的非脑原性是由于其细胞内源性IL-10产生的假设。我们还将测试Bhlhe40作为控制自身反应性TH细胞致病性的基因的直接转录调节因子的假设，并确定这种转录调节所需的Bhlhe40蛋白的结构特征。在目标2中，我们将使用Bhlhe40-绿色荧光蛋白(GFP)报告小鼠来鉴定诱导Bhlhe40在T细胞中表达的信号，并验证Bhlhe40表达决定自身反应性T细胞致病性的假设。这些研究将有助于我们理解T细胞是如何获得自身侵袭性效应功能的，并可能确定Bhlhe40是治疗自身免疫性疾病的新治疗靶点。