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

基本信息

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
项目类别：
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

项目摘要

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 CD8 T细胞在破坏产生胰岛素的胰腺β细胞的破坏中起关键作用糖尿病（T1DM）。特异性地消除β细胞反应性CD8 T细胞将是很好的治疗价值;它将防止易感人群的糖尿病发育，同时离开其余的免疫力系统基本完整。但是，我们尚未完全了解这些致病性自动反应性CD8 T细胞的开发和维护。这个长期目标项目是为了阐明调节β细胞反应性CD8 T细胞分化和功能的机制。 CD4 T细胞和CD8 T细胞都需要开发T1DM。最近的工作发现了细胞因子IL-21作为CD4 T细胞产生的临界信号，以帮助CD8 T细胞促进糖尿病进展。但是，IL-21对β细胞反应性CD8 T细胞功能的直接影响和信号事件引起这一点目前未知。我们的初步数据表明IL-21影响转录因子BATF，这可能与T细胞受体刺激诱导的IRF4 TO协调调节CD8 T细胞中的转录程序。这使我们假设维持β细胞反应性CD8 T细胞功能需要BATF和IRF4。在AIM 1中，我们将确定CD4 T细胞衍生的IL-21有助于自动反应的机制 T1DM中的CD8 T细胞。 CD4 T细胞衍生的IL-21对CD8 T细胞功能和BATF表达的影响将在体内确定。然后，在没有IL-21的情况下，BATF在不存在IL-21的情况下挽救CD8 T细胞功能的能力将是在此过程中测试了BATF和IRF4之间物理相互作用的要求。在AIM 2中，我们将阐明BATF-IRF4介导的CD8 T细胞的分子机制糖尿病活性。这些实验将确定BATF和IRF4是否表达参与CD8 T细胞分化和效应子功能的基因。此外，他们将测试BATF和IRF4是否两者都与这些基因的顺式调节元件结合。该建议将有助于我们了解β细胞反应性CD8 T细胞如何在 T1DM的发病机理。这符合NIDDK的使命，因为该项目的结果可能导致将BATF-IRF4相互作用鉴定为治疗或预防的新型治疗靶标 t1dm。