The role of IL-27 signaling in the accumulation and sustained effector function of autoreactive CD8 T cells in type 1 diabetes

IL-27 信号传导在 1 型糖尿病自身反应性 CD8 T 细胞积累和持续效应功能中的作用

• 批准号: 9757557
• 负责人: Ashley Ciecko
• 金额: $ 4.5万
• 依托单位: MEDICAL COLLEGE OF WISCONSIN
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-03-01 至 2022-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9757557
• 关键词: Affect; Antigen-Presenting Cells; Autoimmune Diseases; Beta Cell; Bone Marrow; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; Candidate Disease Gene; Cell physiology; Chimera organism; Chromosomes, Human, Pair 16; Complex; Data; Dendritic Cells; Development; Diabetes Mellitus; Disease; Disease susceptibility; Effector Cell; Environment; Environmental Risk Factor; Fellowship; Flow Cytometry; Frequencies; Genes; Genetic; Genetic Predisposition to Disease; Goals; Heterogeneity; Homing; Human; Human Genome; IL27RA gene; Impairment; In Vitro; Inbred NOD Mice; Incidence; Inflammatory; Insulin; Insulin-Dependent Diabetes Mellitus; Interleukins; Islets of Langerhans; Knowledge; Lead; Link; Measures; Mediating; Mission; Modeling; Molecular; Mus; Myelogenous; National Institute of Diabetes and Digestive and Kidney Diseases; Non obese; Pathogenesis; Pathogenicity; Phenotype; Play; Predisposition; Prevention; Process; Production; Quantitative Trait Loci; Rag1 Mouse; Research Personnel; Role; Signal Pathway; Signal Transduction; Structure; Structure of beta Cell of islet; System; T-Cell Activation; T-Cell Receptor; T-Lymphocyte; T-Lymphocyte Subsets; Testing; Transgenic Organisms; Work; autoreactive B cell; autoreactivity; career; cell injury; chronic autoimmune disease; cytokine; diabetic; diabetogenic; experimental study; genome wide association study; in vivo; islet; macrophage; new therapeutic target; pathogen; programs; single-cell RNA sequencing

Project Summary Type I diabetes (T1D) is a chronic autoimmune disease in which T cells destroy insulin-producing pancreatic β cells. T1D results from a complex interaction between genetic predisposition and environmental factors. Completely defining the genetic and environmental factors that contribute to disease susceptibility is crucial to finding successful therapies in the treatment and prevention of T1D. Human IL27 (encodes a subunit of the cytokine interleukin (IL)-27) is a T1D candidate gene located in a susceptibility region on chromosome 16. The function of IL-27 in T1D pathogenesis is unknown. The long-term goal of this project is to define the role of IL-27 in the progression of T1D. CD8 T cells are the main effectors mediating β cell damage but they require help from CD4 T cells. Previous studies with both human and mouse have shown that IL-27 signaling can regulate T cell function. Our lab has generated non-obese diabetic (NOD) mice deficient in IL-27 or IL-27 receptor (IL-27Ra) and demonstrated that IL-27 signaling in both CD4 and CD8 T cells is important for diabetes development. Additionally, our preliminary data show that lack of direct IL-27 signaling results in decreased CD8 T cell frequency, proliferation, and cytokine production in the pancreatic islets. Together these observations lead us to hypothesize that IL-27 signaling is important for the accumulation and sustained effector function of autoreactive CD8 T cells. In Aim 1, we will determine the mechanism by which IL-27 signaling directly promotes the accumulation and sustained effector function of autoreactive CD8 T cells. These experiments will test the intrinsic effect of IL-27 signaling on CD8 T cell homing and differentiation into pathogenic effectors. In Aim 2, we will determine the mechanism by which direct IL-27 signaling promotes the ability of CD4 T cells to help autoreactive CD8 T cells. Pathogenic CD8 T cells require help from CD4 T cells for activation and propagation. Therefore, these experiments will test the effect of CD4 T cell- intrinsic IL-27 signaling on the differentiation of CD8 T cells in the pancreatic islets. This proposal will advance our understanding of the differentiation and effector function of autoreactive CD8 T cells during the progression of T1D. This is in line with the mission of NIDDK, as the results of this project could lead to identification of the IL-27 signaling pathway as a novel therapeutic target for the treatment or prevention of T1D.

项目摘要 I型糖尿病（T1 D）是一种慢性自身免疫性疾病，其中T细胞破坏产生胰岛素的胰腺β-胰岛素受体。 细胞T1 D是遗传易感性和环境因素之间复杂相互作用的结果。 完全确定导致疾病易感性的遗传和环境因素对于 寻找治疗和预防T1 D的成功疗法。人IL 27（编码IL 27的亚基） 细胞因子白细胞介素（IL）-27）是位于染色体16上的易感性区域中的T1 D候选基因。的 IL-27在T1 D发病机制中的功能尚不清楚。该项目的长期目标是确定 IL-27在T1 D进展中的作用CD 8 T细胞是介导β细胞损伤的主要效应子，但它们需要免疫调节。 CD 4 T细胞的帮助先前对人类和小鼠的研究表明，IL-27信号转导可以 调节T细胞功能。我们的实验室已经产生了IL-27或IL-27缺陷的非肥胖糖尿病（NOD）小鼠 受体（IL-27 Ra），并证明了CD 4和CD 8 T细胞中的IL-27信号传导对于 糖尿病发展此外，我们的初步数据表明，缺乏直接的IL-27信号转导导致 降低胰岛中CD 8 T细胞频率、增殖和细胞因子产生。综合这些 观察结果使我们假设IL-27信号传导对于IL-27的积累和持续表达是重要的。 自身反应性CD 8 T细胞的效应子功能。在目标1中，我们将确定IL-27 信号直接促进自身反应性CD 8 T细胞的积累和持续效应功能， 细胞这些实验将测试IL-27信号传导对CD 8 T细胞归巢和分化的内在作用 转化为致病效应子。在目标2中，我们将确定直接IL-27信号转导的机制。 促进CD 4 T细胞帮助自身反应性CD 8 T细胞的能力。CD 8 T细胞需要帮助 用于活化和增殖。因此，这些实验将测试CD 4 T细胞的作用- 内在IL-27信号传导对胰岛中CD 8 T细胞分化的影响。该提案将推动 我们对自身反应性CD 8 T细胞的分化和效应功能的理解， 的T1 D。这符合NIDDK的使命，因为这一项目的结果可能导致查明 IL-27信号通路作为治疗或预防T1 D的新治疗靶点。