Shaping diabetogenic T cells by IL-27 in type 1 diabetes

IL-27 在 1 型糖尿病中塑造致糖尿病 T 细胞

基本信息

批准号：
10241954
负责人：
Yi-Guang Chen
金额：
$ 36.53万
依托单位：
MEDICAL COLLEGE OF WISCONSIN
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-08-22 至 2023-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10241954
关键词：
Antigens Autoimmune Autoimmune Diseases B cell differentiation B-Lymphocytes Beta Cell Binding Bone Marrow CD4 Positive T Lymphocytes CD8-Positive T-Lymphocytes CD8B1 gene Candidate Disease Gene Cell physiology Cells Chimera organism Cytotoxic T-Lymphocytes Dendritic Cells Development Diabetes Mellitus Disease Environmental Risk Factor FOXP3 gene Future Genes Genetic Predisposition to Disease Genetic study Homing Human Human Genetics Human Genome IL6ST gene Immune Immune system Impairment Inbred NOD Mice Incidence Injections Insulin Insulin-Dependent Diabetes Mellitus Islets of Langerhans Knowledge Life Link Mus Non obese Orthologous Gene Pancreas Pathogenicity Population Rag1 Mouse Regulatory T-Lymphocyte Reporter Resistance Role Shapes Signal Transduction Structure of beta Cell of islet Supporting Cell T cell therapy T-Cell Receptor T-Lymphocyte T-Lymphocyte Subsets Testing Transgenic Organisms Venus Work autoimmune pathogenesis autoreactive B cell autoreactive T cell autoreactivity base cytokine diabetic diabetogenic experimental study genome wide association study immune function islet lymph nodes macrophage mouse model novel therapeutic intervention nuclease programs receptor response single-cell RNA sequencing

项目摘要

PROJECT SUMMARY Type 1 diabetes (T1D) is a life-long disease requiring daily injections of exogenous insulin. The incidence of T1D has been increasing worldwide in recent decades. Genetic susceptibility and environmental factors interactively contribute to T1D development. Human genetic studies have identified more than 50 loci significantly linked to T1D. However, our knowledge of the underlying genes within these regions that independently or cooperatively influence cellular processes leading to the destruction of insulin producing pancreatic beta-cells is incomplete. To fill this gap, we used nuclease based approaches to target the murine orthologs of human T1D candidate genes directly in nonobese diabetic (NOD) mice to seek functional evidence of their roles in diabetes development. In this effort, we discovered that Il27 is essential for diabetes development in NOD mice. Both CD4 and CD8 T cells are required for T1D development. How beta-cell autoreactive T cells are activated, accumulate, and maintain their effector function during T1D progression has not been fully defined. In this application we will determine the mechanisms by which IL-27 impacts T1D through its direct effects on T cells. IL-27 exerts diverse immunological functions by binding to its receptors (IL-27Ra and gp130 heterodimers) expressed on many immune cells, including macrophages, dendritic cells (DCs), B cells, and T cells. We showed here that both NOD.Il27-/- and NOD.Il27ra-/- mice, respectively lacking IL-27 and its receptor, were completely resistant to diabetes, indicating a critical role of IL-27 signaling in T1D development. Our studies also demonstrated that IL-27 produced by macrophages and/or DCs was sufficient to drive T1D but their responses to IL-27 were not important for diabetes development. Total T cells isolated from NOD and NOD.Il27-/- mice were similarly diabetogenic when transferred into IL-27-sufficient NOD.Rag1-/- recipients. Thus, β-cell autoreactive T cells are present in NOD.Il27-/- mice, but their pathogenic activity cannot be induced or sustained in the absence of IL-27. In contrast, total T cells isolated from NOD.Il27ra-/- mice did not induce T1D in NOD.Rag1-/- recipients, indicating that direct IL-27 signaling in T cells promotes diabetes development. Using a mixed CD4 and CD8 T cell transfer approach, we further demonstrated that IL-27 signaling in both CD4 and CD8 T cells is important for T1D progression. One important diabetogenic activity of CD4 T cells is to provide help to autoreactive CD8 T cells that directly recognize and kill insulin-producing beta-cells. Therefore, we hypothesize that IL-27 is important for the accumulation and sustained effector function of beta-cell autoreactive CD8 T cells by directly acting on them and indirectly through enhancing the helper function of CD4 T cells. We propose the following aims to test this hypothesis. (1) To identify the mechanisms by which IL-27 intrinsically promotes beta-cell autoreactive CD8 T cells in T1D. (2) To determine the function of IL-27 signaling in CD4 T cells for supporting autoreactive CD8 T effectors in T1D. Completion of the proposed experiments will lay the framework for future human studies.

项目摘要 1型糖尿病（T1D）是一种终身疾病，需要每天注射外源性胰岛素。事件近几十年来，T1D在全球范围内一直在增加。遗传敏感性和环境因素互动有助于T1D开发。人类遗传研究已经确定了50多个基因座与T1D显着相关。但是，我们对这些地区中基础基因的了解独立或合作影响导致胰岛素产生破坏的细胞过程胰腺β细胞不完整。为了填补这一空白，我们使用了基于核酸酶的方法来靶向鼠直接在非肥胖糖尿病（NOD）小鼠中的人类T1D候选基因的直系同源物寻求功能他们在糖尿病发育中作用的证据。在这项工作中，我们发现IL27对于糖尿病发育至关重要点头小鼠的发育。 T1D发育需要CD4和CD8 T细胞。如何Beta细胞自动反应性T细胞被激活，丙烯酸并在T1D进展过程中维持其效应子功能未完全定义。在此应用中，我们将确定IL-27影响T1D的机制通过其对T细胞的直接影响。 IL-27通过与其接收器结合来执行潜水员的免疫功能（IL-27RA和GP130异二聚体）在许多免疫细胞上表达，包括巨噬细胞，树突状细胞（DC），B细胞和T细胞。我们在这里表明nod.il27 - / - 和nod.il27ra - / - 小鼠缺乏IL-27及其受体完全抵抗糖尿病，表明IL-27信号的关键作用在T1D开发中。我们的研究还表明，巨噬细胞和/或DC产生的IL-27是足以驱动T1D，但它们对IL-27的反应对于糖尿病发育并不重要。总T细胞从NOD和NOD.IL27 - / - 小鼠中分离出来时，当转移到IL-27充分的情况下时也是糖尿病的 nod.rag1 - / - 收件人。 β细胞自动反应性T细胞存在于NOD.IL27 - / - 小鼠中，但它们的致病性在没有IL-27的情况下，无法诱导或维持活性。相比之下，总的T细胞从 NOD.IL27RA - / - 小鼠在Nod.rag1 - / - 受体中不影响T1D，表明T中直接IL-27信号传导细胞促进糖尿病发育。使用混合的CD4和CD8 T细胞转移方法，我们进一步证明CD4和CD8 T细胞中的IL-27信号对于T1D进展很重要。一 CD4 T细胞的重要糖尿病活性是为直接的自动反应性CD8 T细胞提供帮助公认并杀死产生胰岛素的β细胞。因此，我们假设IL-27对通过直接作用于β细胞自动反应性CD8 T细胞的积累和持续效应子功能并通过增强CD4 T细胞的辅助功能间接。我们提出以下目的来测试这一点假设。（1）确定IL-27本质上促进β细胞自动反应性CD8 T的机制 T1D中的细胞。（2）确定CD4 T细胞中IL-27信号传导的功能，以支持自动反应性CD8 T T1D的效应子。提议的实验的完成将为未来的人类研究奠定框架。