Single Cell Genomics to Resolve Control of Immune Cell Function During Type 1 Diabetes

项目总结 针对胰岛β细胞抗原的T细胞驱动自身免疫反应导致1型糖尿病 (T1D)。在T1D发病期间，多种免疫细胞类型渗入胰岛，但每种免疫细胞类型的渗入 单个胰岛在单个小鼠或人体内有很大的不同。此外，两国之间的互动 在个体的微环境中，免疫细胞和常驻胰岛细胞的免疫反应不同。 胰岛从渗透和最初激活到最终破坏之前的一段调整期。更好的 了解控制胰岛自身反应性T细胞功能的因素可能会导致治疗T1D 瞄准导致疾病的潜在机制。根据我们已发表的工作和新的初步数据， 我们的中心假设是，自体反应性CD8+T细胞对β细胞的破坏是由激活 碱性区域亮氨酸拉链(BZIP)转录因子对胰岛抗原和局部细胞的反应 微环境。我们预测，这些程序是由细胞在CD8+T细胞中差异诱导的 每个单独的胰岛的微环境。我们提出了两个目标来检验这些预测在T1D发病期间 使用新的单细胞功能基因组学方法的NOD小鼠。在目标1中，我们将确定贡献 BZIP转录因子家族中与胰腺中自身反应性T细胞功能有关的基因。在目标2中，我们将确定 巨噬细胞对单独胰岛间单个细胞转录程序的影响 微环境。我们研究的预期结果将解决有关根本问题的悬而未决的问题 自身免疫性疾病中控制T细胞活性和免疫细胞相互作用的机制。

PROJECT SUMMARY T cells specific for pancreatic beta cell antigens drive an autoimmune response leading to type 1 diabetes (T1D). During the onset of T1D, many immune cell types infiltrate into pancreatic islets, but the infiltration of each individual islet varies substantially within an individual mouse or human. Additionally, the interactions between immune cells and resident islet cells vary over the immune response within the microenvironment of an individual islet from infiltration and initial activation to a period of regulation before eventual destruction. A better understanding of factors that control autoreactive T cell function in the islets could lead to therapies for T1D that target the underlying mechanisms that cause disease. Based on our published work and new preliminary data, our central hypothesis is that autoreactive CD8+ T cell destruction of beta cells is determined by activation of the basic region leucine zipper (bZIP) transcription factors in response to the islet antigens and the local cellular microenvironment. We predict that these programs are differentially induced in CD8+ T cells by the cellular microenvironment of each individual islet. We propose two aims to test these predictions during onset of T1D in NOD mice using novel single cell functional genomics approaches. In Aim 1 we will determine the contribution of the bZIP transcription factors family to autoreactive T cell function in the pancreas. In Aim 2 we will determine impact of macrophages on the transcriptional programs of individual cells between separate pancreatic islet microenvironments. The expected results of our study will address unanswered questions about the fundamental mechanisms controlling T cell activity and immune cell interplay during autoimmune disease.