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

项目摘要 胰腺β细胞抗原特异性T细胞驱动导致1型糖尿病的自身免疫反应 （T1D）。在T1D发病期间，许多免疫细胞类型浸润到胰岛中，但每种免疫细胞类型的浸润都是不稳定的。 单个胰岛在单个小鼠或人中变化很大。此外， 免疫细胞和常驻胰岛细胞在个体微环境内的免疫应答上不同 胰岛从浸润和初始激活到最终破坏前的一段调节期。更好的 了解控制胰岛中自身反应性T细胞功能的因素可能导致T1D的治疗， 针对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，自身反应性CD8+ T细胞对β细胞的破坏是由β细胞的活化决定的。 碱性区亮氨酸拉链（bZIP）转录因子对胰岛抗原和局部细胞免疫应答的反应。 微环境我们预测这些程序在CD8+ T细胞中是由细胞因子诱导的。 每一个人的微环境。我们提出了两个目标，以测试这些预测在发病的T1D， 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 bZIP转录因子家族与胰腺中自身反应性T细胞功能的关系。在目标2中，我们将确定 巨噬细胞对胰岛细胞转录程序的影响 微环境我们的研究的预期结果将解决有关基本的未回答的问题， 在自身免疫性疾病期间控制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.