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

• 批准号: 10736476
• 负责人: Rachel S Friedman
• 金额: $ 45.44万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-01-04 至 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10736476
• 关键词: Address; Antigen Presentation; Antigen Presentation Pathway; Antigens; Apoptotic; Autoantibodies; Autoimmune; Autoimmunity; Beta Cell; Cell Communication; Cell Death; Cell physiology; Cells; Coupled; Data; Dendritic Cells; Diagnosis; Disease; Disease Progression; Environment; Equilibrium; FRAP1 gene; Flow Cytometry; Gene Expression Profile; Goals; Human; Image Cytometry; Immune; Immunity; Inflammation Mediators; Inflammatory; Insulin; Insulin-Dependent Diabetes Mellitus; Interleukin-6; Islet Cell; Islets of Langerhans; Knowledge; Lead; Lymphocyte; Macrophage; Mediating; Molecular; Mus; Myelogenous; Myeloid Cells; NF-kappa B; Organ Donor; Pancreas; Pathogenesis; Pathogenicity; Pathway interactions; Patients; Play; Population; Process; Production; Receptor Signaling; Regulatory T-Lymphocyte; Resistance; Role; Sampling; Severities; Signal Transduction; T cell response; T-Cell Activation; T-Cell Receptor; T-Lymphocyte; T-Lymphocyte Subsets; Therapeutic Intervention; Transcription Factor AP-1; autoreactive T cell; cell regeneration; cytokine; effector T cell; experimental study; immunoregulation; improved; insulin dependent diabetes mellitus onset; insulitis; islet; islet autoimmunity; monocyte; mouse model; new therapeutic target; non-diabetic; nuclear factors of activated T-cells; permissiveness; prevent; protective pathway; single-cell RNA sequencing; uptake

PROJECT SUMMARY In type 1 diabetes (T1D), autoimmunity is established and self-perpetuating within the islets at diagnosis. Autoreactive T cells in T1D patients destroy endogenous and grafted beta cells, yet there is a gap in knowledge about the mechanisms by which T cell pathogenesis is modulated in the islets. Evidence from mouse models of T1D and human samples suggest that myeloid cells play an essential role in this process. The myeloid compartment represents the largest immune population in non-diabetic and many T1D human islets. Islet myeloid cells can contribute to islet destruction or protection, yet a significant gap in knowledge remains about how the islet myeloid compartment plays such divergent roles in islet autoimmunity during T1D progression. We have shown that Mertk signaling in islet myeloid cells suppresses autoreactive T cell responsiveness to antigen and prevents rapid progression of T1D. Mertk mediates apoptotic cell uptake (efferocytosis), and its signaling is immunoregulatory. However, we do not yet understand the mechanisms by which Mertk signaling in islet myeloid cells suppresses the ability of autoreactive T cells to respond to locally presented antigen. Our scRNA-seq analyses of myeloid cells from the islets of non-diabetic and T1D organ donors support that, similar to our mouse data, efferocytosis is enhanced and antigen processing and presentation are suppressed during the active period of disease following T1D onset. Thus, our overarching hypothesis is that in the islets during T1D, stimulatory myeloid cell subsets promote pathogenic T cell functions through antigenic stimulation and inhibitory islet myeloid cell subsets suppress the pathogenic T cells in a manner that is dependent upon Mertk mediated efferocytosis within the pancreatic islet. To begin to address the gaps in knowledge about islet myeloid cell function, we propose the following aims: Aim 1: Elucidate the mechanisms by which Mertk expressing myeloid cells modulate effector and regulatory T cell responses in the islets. Aim 2: Characterize the myeloid cell subsets that actively present antigen to effector and regulatory T cells in mouse islets and how this is altered by Mertk signaling. Aim 3: Determine the human islet myeloid subsets that perform Mertk-mediated efferocytosis and drive T cell signaling in human islets. The successful completion of this proposal will result in: (1) an improved understanding of the mechanisms used by Mertk- expressing islet myeloid cells to suppress the islet T cell response, (2) an enhanced understanding of pancreatic islet myeloid cell subsets and pathways that drive pathogenic T cell activation versus those that regulate islet autoimmunity and (3) identification of novel therapeutic targets to potentially skew the autoim- mune T cell response toward protective immunity in type 1 diabetes.

项目摘要 在1型糖尿病（T1 D）中，自身免疫在诊断时在胰岛内建立并自我延续。 T1 D患者中的自身反应性T细胞破坏内源性和移植的β细胞，但在这方面存在差距。 了解T细胞发病机制在胰岛中的调节。证据 T1 D的小鼠模型和人类样品表明骨髓细胞在该过程中起重要作用。 髓样区室代表非糖尿病和许多T1 D人中最大的免疫群体。 小岛胰岛髓样细胞可以促进胰岛破坏或保护，但在知识上存在重大差距 关于胰岛髓样区室如何在T1 D期间胰岛自身免疫中发挥如此不同的作用， 进展我们已经证明胰岛骨髓细胞中的Mertk信号传导抑制自身反应性T细胞 T1 D是一种对抗原的反应性，并防止T1 D的快速进展。Mertk介导凋亡细胞摄取 （红细胞增多症），并且其信号传导是免疫调节的。然而，我们还不了解这些机制， 胰岛髓样细胞中的Mertk信号传导抑制自身反应性T细胞局部应答的能力， 呈现抗原。我们对来自非糖尿病和T1 D器官胰岛的髓样细胞的scRNA-seq分析 与我们的小鼠数据类似，供体支持，红细胞增多症增强，抗原加工和 在T1 D发作后的疾病活动期期间，这些表现受到抑制。因此， 一种假说认为，在T1 D期间的胰岛中，刺激性骨髓细胞亚群促进致病性T细胞功能 通过抗原刺激和抑制性胰岛髓样细胞亚群， 依赖于胰岛内Mertk介导的巨噬细胞增多的方式。开始处理 针对目前对胰岛髓样细胞功能认识上的不足，我们提出以下目标：目标1：阐明胰岛髓样细胞功能， 表达Mertk的髓样细胞调节免疫系统中效应和调节性T细胞应答的机制 小岛目的2：鉴定主动提呈抗原给效应和调节T细胞的髓系细胞亚群 小鼠胰岛中的细胞以及Mertk信号如何改变这一点。目的3：测定人胰岛髓样细胞 在人类胰岛中进行Mertk介导的红细胞增多并驱动T细胞信号传导的亚群。成功 完成本提案将导致：（1）更好地理解Mertk使用的机制- 表达胰岛髓样细胞以抑制胰岛T细胞反应，（2）增强对 胰岛髓样细胞亚群和驱动致病性T细胞活化的途径与 调节胰岛自身免疫和（3）识别新的治疗靶点，以潜在地扭曲自身免疫， 1型糖尿病患者免疫T细胞对保护性免疫的反应