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: 9886072
• 负责人: Ashley Ciecko
• 金额: $ 3.71万
• 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 2020-10-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9886072
• 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; Chromosome 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; diabetes pathogenesis; 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(T1D)是一种慢性自身免疫性疾病，T细胞破坏产生胰岛素的胰腺β 细胞。T1D是遗传易感性和环境因素复杂交互作用的结果。 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T1D的成功疗法。人类IL27(编码人类白细胞介素27的亚基 细胞因子白介素27(IL-27)是一种T1D候选基因，位于16号染色体的易感区域。 IL-27在T1D发病机制中的作用尚不清楚。该项目的长期目标是定义 IL-27在T1D发病过程中的作用CD8T细胞是介导β细胞损伤的主要效应者，但它们需要 来自CD4T细胞的帮助。之前对人类和小鼠的研究表明，IL-27信号可以 调节T细胞功能。我们的实验室已经培育出IL-27或IL-27缺乏的非肥胖糖尿病(NOD)小鼠 受体(IL-27Ra)，并证明了在CD_4和CD_8 T细胞中IL-27信号转导在 糖尿病的发展。此外，我们的初步数据显示，缺乏直接的IL-27信号导致 降低胰岛CD8T细胞的频率、增殖和细胞因子的产生。把这些放在一起 观察结果使我们假设，IL-27信号对血液中IL-27的积累和持续 自身反应性CD8 T细胞的效应功能。在目标1中，我们将确定IL-27 信号转导直接促进自身反应性CD8T的蓄积和持续效应功能 细胞。这些实验将测试IL-27信号对CD8 T细胞归巢和分化的内在影响 转化为致病效应器。在目标2中，我们将确定引导IL-27信号的机制 促进CD4T细胞帮助自身反应CD8T细胞的能力。致病CD8 T细胞需要帮助 从CD4T细胞中进行激活和繁殖。因此，这些实验将测试CD4T细胞- 内源性IL-27信号对胰岛CD8 T细胞分化的影响这项提议将会取得进展 自身反应性CD8 T细胞分化及其效应功能的认识 T1D。这与NIDDK的使命是一致的，因为该项目的结果可能导致确定 IL-27信号通路作为治疗或预防T1D的新靶点