BATF-IRF4 complex controls transcriptional regulation and effector function of autoreactive CD8 T cells in type 1 diabetes

BATF-IRF4 复合物控制 1 型糖尿病中自身反应性 CD8 T 细胞的转录调节和效应器功能

• 批准号: 9191056
• 负责人: David Schauder
• 金额: $ 4.57万
• 依托单位: VERSITI WISCONSIN, INC.
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-01 至 2020-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9191056
• 关键词: Antigens; Autoimmune Process; Beta Cell; Binding; CD4 Positive T Lymphocytes; CD8B1 gene; Cell Differentiation process; Cell Survival; Cell physiology; Cells; Chronic; Complex; Data; Development; Diabetes Mellitus; Disease Progression; Event; Exhibits; Exposure to; Fellowship; Frequencies; Gene Expression; Genes; Goals; Hyperglycemia; IRF4 gene; Immune system; Inbred NOD Mice; Individual; Insulin; Insulin-Dependent Diabetes Mellitus; Lead; Left; Maintenance; Mediating; Mission; Modeling; Molecular; Molecular Genetics; Mus; National Institute of Diabetes and Digestive and Kidney Diseases; Non obese; Pathogenesis; Peptides; Phenotype; Play; Prevention; Process; Proteins; Rag1 Mouse; Regulatory Element; Rest; Role; Signal Transduction; Structure of beta Cell of islet; T cell differentiation; T-Cell Receptor; T-Lymphocyte; Testing; Therapeutic; Transcriptional Regulation; Work; cell injury; chronic autoimmune disease; cytokine; cytotoxic; diabetic; diabetogenic; exhaust; human disease; in vivo; interleukin-21 receptor; mouse model; mutant; new therapeutic target; overexpression; prevent; programs; protein expression; research study; transcription factor

Project Summary CD8 T cells play a critical role in the destruction of insulin-producing pancreatic β cells leading to type 1 diabetes mellitus (T1DM). Specifically eliminating β cell-reactive CD8 T cells would be of great therapeutic value; it would prevent diabetes development in susceptible individuals, while leaving the rest of their immune systems largely intact. However, we do not yet fully understand the molecular details underlying the development and maintenance of these pathogenic autoreactive CD8 T cells. The long-term goal of this project is to elucidate the mechanisms regulating β cell-reactive CD8 T cell differentiation and function. CD4 T cells and CD8 T cells are both required for the development of T1DM. Recent work uncovered the cytokine IL-21 as a critical signal produced by CD4 T cells to help CD8 T cells promote diabetes progression. However, the direct effects of IL-21 on β cell-reactive CD8 T cell function and the signaling events causing this are currently unknown. Our preliminary data suggest that IL-21 induces expression of the transcription factor BATF, and that this might cooperate with T cell receptor stimulation-induced IRF4 to regulate a transcriptional program in CD8 T cells. This leads us to hypothesize that the interaction between BATF and IRF4 is required for the maintenance of β cell-reactive CD8 T cell function. In Aim 1, we will determine the mechanism by which CD4 T cell-derived IL-21 helps autoreactive CD8 T cells in T1DM. The effect of CD4 T cell-derived IL-21 on CD8 T cell function and BATF expression will be determined in vivo. Then, the ability of BATF to rescue CD8 T cell function in the absence of IL-21 will be tested, as well as the requirement of the physical interaction between BATF and IRF4 in this process. In Aim 2, we will elucidate the molecular mechanism of BATF-IRF4-mediated CD8 T cell diabetogenic activity. These experiments will determine if BATF and IRF4 are both required for expression of genes involved in CD8 T cell differentiation and effector function. Furthermore, they will test if BATF and IRF4 both bind to cis-regulatory elements of these genes. This proposal will help us understand how β cell-reactive CD8 T cells differentiate and function during the pathogenesis of T1DM. This is in line with the mission of NIDDK, as the results of this project could lead to identification of the BATF-IRF4 interaction as a novel therapeutic target for the treatment or prevention of T1DM.

项目摘要 CD 8 T细胞在破坏产生胰岛素的胰腺β细胞中起关键作用，导致1型糖尿病。 糖尿病（T1 DM）。特异性消除β细胞反应性CD 8 T细胞将具有很好的治疗效果。 价值;它将防止易感个体的糖尿病发展，同时使其其余的免疫系统 系统基本完好。然而，我们还没有完全了解这些分子的细节。 这些致病性自身反应性CD 8 T细胞的发展和维持。长期目标是 目的是阐明β细胞反应性CD 8 T细胞分化和功能的调控机制。 CD 4 T细胞和CD 8 T细胞都是T1 DM发展所必需的。近期工作发现 细胞因子IL-21作为CD 4 T细胞产生的关键信号，帮助CD 8 T细胞促进糖尿病 进展然而，IL-21对β细胞反应性CD 8 T细胞功能的直接作用和信号传导事件是不确定的。 造成这种情况的原因目前尚不清楚。我们的初步数据表明，IL-21诱导表达， 转录因子BATF，这可能与T细胞受体刺激诱导的IRF 4合作， 调节CD 8 T细胞中的转录程序。这使我们假设， BATF和IRF 4是维持β细胞反应性CD 8 T细胞功能所必需的。 在目标1中，我们将确定CD 4 T细胞来源的IL-21帮助自身反应性免疫应答的机制。 T1 DM中的CD 8 T细胞。CD 4 T细胞来源的IL-21对CD 8 T细胞功能和BATF表达的影响将被证实。 在体内测定。然后，在不存在IL-21的情况下，将评估BATF拯救CD 8 T细胞功能的能力。 测试，以及在这个过程中BATF和IRF 4之间的物理相互作用的要求。 目的二：阐明BATF-IRF 4介导的CD 8 T细胞增殖的分子机制 致糖尿病活性这些实验将确定BATF和IRF 4是否都是表达 参与CD 8 T细胞分化和效应子功能的基因。此外，他们将测试BATF和IRF 4是否 两者都与这些基因的顺式调节元件结合。 这一提议将帮助我们了解β细胞反应性CD 8 T细胞在免疫过程中如何分化和发挥作用。 T1 DM的发病机制。这符合NIDDK的使命，因为该项目的结果可能导致 鉴定BATF-IRF 4相互作用作为治疗或预防的新治疗靶点 关于T1 DM