MerTK Mediated T Cell Suppression in the Pancreatic Islets During Type 1 Diabetes

1 型糖尿病期间 MerTK 介导的胰岛 T 细胞抑制

基本信息

批准号：
9218916
负责人：
Rachel S Friedman
金额：
$ 51.29万
依托单位：
NATIONAL JEWISH HEALTH
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-01-04 至 2021-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9218916
关键词：
Address Antibodies Antigen-Presenting Cells Apoptotic Autoantibodies Beta Cell Blood Glucose CD11c Antigens Cells Complications of Diabetes Mellitus Data Disease Disease Progression Family Flow Cytometry Gene Expression Genetic Goals Human ITGAX gene Imaging Techniques Immune Immune response Immune system Inbred NOD Mice Individual Infiltration Insulin Insulin-Dependent Diabetes Mellitus Islets of Langerhans Knock-out Knowledge Leukocytes Mediating Microscopy Modeling Mononuclear Non obese Pancreas Pathogenicity Pathway interactions Patients Phagocytes Phase Population Production Receptor Protein-Tyrosine Kinases Regulation Relapse Role Sampling Signal Pathway Signal Transduction T-Lymphocyte Techniques Testing Therapeutic Time Translating Work base blood glucose regulation cell behavior cytokine diabetic diabetic patient in vivo insulin dependent diabetes mellitus onset interest islet monocyte novel prevent transcriptome sequencing two-photon uptake

项目摘要

PROJECT SUMMARY: When type 1 diabetes (T1D) patients present with disease, their immune system has already destroyed most of the beta cells in their pancreatic islets. Remaining insulin-producing islets may already be infiltrated with leukocytes, but remaining beta cell mass is instrumental for maintaining blood glucose control, leading to fewer diabetes-related complications. Therefore, controlling the immune response in the islets, particularly T cells, is of paramount importance for preserving remaining insulin production and preventing T1D progression. Our work has shown that the immune response in the islets is temporally regulated. Pathogenic T cell stimulation within the islets occurs early in islet infiltration. However, as islet infiltration advances, T cell restimulation in the islets is at least transiently suppressed, through an undefined mechanism. Our preliminary data depleting CD11c+ cells indicate that CD11c+ cells are responsible for this suppression of T cell restimulation in the islets. Islet CD11c+ cells have differing effects on T cells as islet infiltration progresses, suggesting that islet CD11c+ populations might differ over time. However, there is a gap in knowledge about the specific CD11c+ cell subsets that are present in the islets over the course of islet infiltration, the role of each CD11c+ subset in modulating T cell pathogenicity in the islets, and the mechanisms of CD11c+ cell-mediated T cell suppression in the islets. We found an islet-infiltrating CD11c+ population that expresses MerTK. MerTK is a receptor tyrosine kinase that mediates apoptotic cell uptake and that has previously been implicated in tolerizing T cells during T1D in NOD mice. Strikingly, our preliminary data show that MerTK inhibition induced rapid T1D onset in asymptomatic NOD mice with advanced islet infiltration. Based on these findings, we hypothesize that a subset of islet-infiltrating CD11c+ cells suppress T cell restimulation and effector function in the islets via a MerTK dependent mechanism. To test this hypothesis, we will address the following aims using a variety of techniques including in vivo 2-photon microscopy, single cell RNA-seq, flow cytometry, and analysis of disease progression. Aim 1: To determine the function of islet-infiltrating CD11c+ cells and of MerTK in suppressing T cell pathogenicity within the islets. Aim 2: To identify islet CD11c+ subsets and determine mechanisms by which CD11c+MerTK+ cells promote tolerance in the islets during T1D. Aim 3: To identify the mononuclear phagocyte populations and MerTK expression in human islets during T1D progression and to determine whether MerTK expression or function is altered in T1D. Understanding the mechanisms of T cell suppression in the islets by addressing these aims could allow us to therapeutically reinforce these pathways to protect beta cells mass, insulin production, and blood glucose control in autoantibody-positive pre-diabetic or new-onset diabetic patients.

项目概要：当 1 型糖尿病 (T1D) 患者发病时，他们的免疫系统已经破坏了大部分胰岛中的β细胞。剩余的产生胰岛素的胰岛可能已经被渗透白细胞，但剩余的β细胞团有助于维持血糖控制，从而减少糖尿病相关并发症。因此，控制胰岛的免疫反应，特别是 T 细胞，是至关重要的。对于保持剩余的胰岛素产生和预防 T1D 进展至关重要。我们的研究表明，胰岛中的免疫反应是受到暂时调节的。致病性 T 细胞刺激胰岛内发生于胰岛浸润的早期。然而，随着胰岛浸润的进展，T细胞的再刺激胰岛至少通过一种未定义的机制暂时受到抑制。我们的初步数据正在耗尽 CD11c+ 细胞表明 CD11c+ 细胞负责抑制胰岛中的 T 细胞再刺激。随着胰岛浸润的进展，胰岛 CD11c+ 细胞对 T 细胞具有不同的影响，表明胰岛 CD11c+ 随着时间的推移，人口可能会有所不同。然而，关于特定 CD11c+ 细胞的知识存在空白胰岛浸润过程中存在于胰岛中的子集，每个 CD11c+ 子集在胰岛浸润过程中的作用调节胰岛中的 T 细胞致病性以及 CD11c+ 细胞介导的 T 细胞抑制机制在小岛上。我们发现了表达 MerTK 的胰岛浸润 CD11c+ 群体。 MerTK 是一种受体酪氨酸激酶，介导凋亡细胞摄取，之前已被认为与 T 细胞耐受有关 NOD 小鼠 T1D 期间。引人注目的是，我们的初步数据表明 MerTK 抑制诱导 T1D 快速发作在具有晚期胰岛浸润的无症状 NOD 小鼠中。基于这些发现，我们假设胰岛浸润 CD11c+ 细胞亚群通过以下方式抑制胰岛中的 T 细胞再刺激和效应功能： MerTK 依赖机制。为了检验这个假设，我们将使用各种方法来实现以下目标技术包括体内 2 光子显微镜、单细胞 RNA-seq、流式细胞术和疾病分析进展。目标 1：确定胰岛浸润 CD11c+ 细胞和 MerTK 在抑制 T 细胞中的功能胰岛内细胞的致病性。目标 2：识别胰岛 CD11c+ 亚群并确定机制其中 CD11c+MerTK+ 细胞可促进 T1D 期间胰岛的耐受性。目标 3：识别单核细胞 T1D 进展期间人类胰岛中的吞噬细胞群和 MerTK 表达，并确定 MerTK 表达或功能在 T1D 中是否发生改变。了解 T 细胞抑制机制在胰岛中，通过解决这些目标可以使我们能够在治疗上加强这些途径以保护β 自身抗体阳性糖尿病前期或新发糖尿病患者的细胞质量、胰岛素产生和血糖控制糖尿病患者。