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

项目摘要 CD8T细胞在破坏胰岛素分泌的胰腺β细胞导致1型糖尿病中起关键作用 糖尿病(T1 DM)。特别是消除β细胞反应性CD8T细胞将具有很好的治疗作用 价值；它将防止易患糖尿病的人患上糖尿病，同时使他们其余的人免疫 系统基本完好无损。然而，我们还没有完全了解背后的分子细节 这些致病的自身反应性CD8 T细胞的发展和维持。这样做的长期目标是 该项目旨在阐明β细胞反应性CD8T细胞分化和功能的调控机制。 CD4T细胞和CD8T细胞都是T1 DM发生发展所必需的。发现的最新工作 细胞因子IL-21作为CD4T细胞产生的关键信号帮助CD8T细胞促进糖尿病 进步。然而，IL-21对β细胞反应性CD8T细胞功能和信号转导事件的直接影响 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诱导血管内皮细胞表达 转录因子BATF，这可能与T细胞受体刺激诱导的IRF4协同作用 调节CD8T细胞的转录程序。这让我们假设， BATF和IRF4是维持β细胞反应性CD8T细胞功能所必需的。 在目标1中，我们将确定CD4T细胞来源的IL-21帮助自身反应的机制 T1 DM患者外周血中CD8T细胞的表达CD4T细胞来源的IL-21对CD8T细胞功能和BATF表达的影响 在体内被确定。那么，在缺乏IL-21的情况下，BATF拯救CD8 T细胞功能的能力将是 测试，以及在此过程中BATF和IRF4之间的物理相互作用的要求。 在目标2中，我们将阐明BATF-IRF4介导的CD8 T细胞的分子机制 促糖尿病活性。这些实验将确定是否都需要BATF和IRF4来表达 参与CD8T细胞分化和效应功能的基因。此外，他们还将测试BATF和IRF4 两者都与这些基因的顺式调控元件相结合。 这一建议将有助于我们了解β细胞反应性CD8T细胞是如何在 T1 DM的发病机制。这与NIDDK的使命是一致的，因为该项目的结果可能导致 确定BATF-IRF4相互作用为治疗或预防的新治疗靶点 对T1 DM患者的影响。

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.