Genetic analysis of islet-infiltrating IL-21-expressing CD4 T cells in type 1 diabetes

1 型糖尿病中胰岛浸润表达 IL-21 的 CD4 T 细胞的遗传分析

• 批准号: 10088384
• 负责人: Yi-Guang Chen
• 金额: $ 19万
• 依托单位: MEDICAL COLLEGE OF WISCONSIN
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-01-24 至 2022-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10088384
• 关键词: Address; Autoimmune Diseases; Autoimmune Process; Autoimmunity; Beta Cell; Blood; C57BL/6 Mouse; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; CRISPR/Cas technology; Candidate Disease Gene; Cell membrane; Cell physiology; Cells; Development; Diabetes Mellitus; Foundations; Frequencies; Genetic; Genetic Engineering; Genetic Transcription; Genetic study; Goals; Heterogeneity; Human; Immune Tolerance; In Vitro; Inbred NOD Mice; Injections; Insulin; Insulin-Dependent Diabetes Mellitus; Investigation; Islets of Langerhans; Knowledge; Molecular; Mouse Strains; Mus; Nature; Non obese; PTPN22 gene; Pathogenicity; Patients; Phenotype; Population; Procedures; Production; Proteins; Reporter; Resistance; Role; Stains; Structure of beta Cell of islet; System; T cell therapy; T-Lymphocyte; T-Lymphocyte Subsets; Testing; Therapeutic; Variant; age related; autoimmune pathogenesis; autoreactive B cell; autoreactivity; blood glucose regulation; cytokine; design; diabetes pathogenesis; diabetic; diabetogenic; effector T cell; genetic analysis; genome wide association study; insight; insulitis; interleukin-21; islet; lymphoid organ; novel; programs; resistant strain; risk variant; single cell analysis; single-cell RNA sequencing; therapeutic target; tool

PROJECT SUMMARY Type 1 diabetes (T1D) is caused by autoimmune destruction of insulin-producing pancreatic beta-cells. Nonobese diabetic (NOD) mice develop spontaneous T1D and have been used extensively to study the genetic and pathogenic mechanisms of this autoimmune disease. Recently, a diabetogenic role of interleukin (IL)-21 has emerged, and higher levels of this cytokine were shown to be expressed by NOD mice compared to the T1D resistant strains. IL-21 is produced by CD4 T cells and its contribution to T1D is in part through its ability to support the survival and function of diabetogenic CD8 T cells that directly kill pancreatic beta-cells. NOD mice have an age dependent accumulation of IL-21+ CD4 T cells in islets. Importantly, NOD mice genetically rendered IL-21-deficient are completely resistant to the development of insulitis and diabetes. Interestingly, NOD islet IL-21+ CD4 T cells have a unique phenotype distinct from that of typical Th17 and Tfh CD4 T cell effector subsets known as the main IL-21 producers. Consistent with a diabetogenic function of IL- 21 in NOD mice, available evidence also supports its role in human T1D. Significantly higher levels of circulating IL-21+ CD4 T cells and IL-21 protein were found in subjects with beta-cell autoimmunity than in healthy controls. How IL-21+ CD4 T cells emerge and accumulate during the progression of T1D in both NOD mice and humans remains largely unknown and therefore deserves further investigation. More than 50 loci have been associated with human T1D by genome wide association studies (GWAS). One of the top risk genes is PTPN22. The human PTPN22 risk allele modulates T cell functions and promotes T1D when introduced into NOD mice. Notably, PTPN22 deficiency on the non-autoimmune prone C57BL/6 mouse strain background has been associated with a higher frequency of Tfh CD4 T cells and their enhanced production of IL-21. Addressing whether PTPN22 regulates diabetes development through modulating the differentiation states of islet IL-21+ CD4 T cells in NOD mice will provide a better understanding of the genetic control of T1D. Our hypothesis is that the ability of beta-cell autoreactive CD4 T cells to produce IL-21 represents a unique differentiation state that is modulated by Ptpn22 variants. We propose the following aims to test this hypothesis. Aim 1. To define the differentiation state of islet-infiltrating IL-21-expressing CD4 T cells by identifying their transcriptional networks using single-cell RNA sequencing. Aim 2. To determine the effects of Ptpn22 variants on the differentiation of islet-infiltrating IL-21-expressing CD4 T cells.

项目摘要 1型糖尿病（T1D）是由胰岛素产生胰岛β细胞的自身免疫性破坏引起的。 非肥胖糖尿病（NOD）小鼠发育自发T1D，已广泛用于研究 这种自身免疫性疾病的遗传和致病机制。最近，白介素的糖尿病作用 （IL）-21已经出现，该细胞因子的水平较高，表明是由NOD小鼠表达的 到T1D抗性菌株。 IL-21由CD4 T细胞产生，其对T1D的贡献部分通过其 能够支持直接杀死胰腺β细胞的糖尿病性CD8 T细胞的存活和功能。 NOD小鼠在胰岛中具有IL-21+ CD4 T细胞的年龄依赖性积累。重要的是，点头小鼠 遗传渲染的IL-21缺陷剂完全抵抗胰岛炎和糖尿病的发展。 有趣的是，点头IL-21+ CD4 T细胞具有与典型TH17和TFH不同的独特表型 CD4 T细胞效应子集被称为主要IL-21生产者。与IL-的糖尿病性功能一致 21在点头小鼠中，可用证据也支持其在人类T1D中的作用。明显更高的水平 在β细胞自身免疫的受试者中发现了循环IL-21+ CD4 T细胞和IL-21蛋白，而不是在 健康控制。 IL-21+ CD4 T细胞在T1D的进展过程中如何出现并积累 小鼠和人类仍然在很大程度上未知，因此值得进一步研究。超过50个基因座 通过基因组广泛关联研究（GWAS）与人类T1D有关。最佳风险之一 基因为PTPN22。人类PTPN22风险等位基因调节T细胞功能并促进T1D 引入点头小鼠。值得注意的是，非自动免疫性易免疫的PTPN22缺乏症 背景与TFH CD4 T细胞的频率更高有关，并增强了其产生 IL-21。解决PTPN22是否通过调节分化来调节糖尿病的发育 NOD小鼠中胰岛IL-21+ CD4 T细胞的状态将更好地理解T1D的遗传控制。 我们的假设是β细胞自动反应性CD4 T细胞产生IL-21的能力代表了独特 由PTPN22变体调节的分化状态。我们提出以下目的来测试这一点 假设。目的1。定义胰岛渗透IL-21的CD4 T细胞的分化状态 使用单细胞RNA测序识别其转录网络。目标2。确定 PTPN22在胰岛渗透IL-21表达CD4 T细胞的分化的变体。

项目成果

Interleukin-27 is essential for type 1 diabetes development and Sjögren syndrome-like inflammation.

• DOI: 10.1016/j.celrep.2021.108725
• 发表时间: 2021-02-02
• 期刊: Cell reports
• 影响因子: 8.8
• 作者: Ciecko AE;Foda B;Barr JY;Ramanathan S;Atkinson MA;Serreze DV;Geurts AM;Lieberman SM;Chen YG
• 通讯作者: Chen YG

CD226 Deletion Reduces Type 1 Diabetes in the NOD Mouse by Impairing Thymocyte Development and Peripheral T Cell Activation.

• DOI: 10.3389/fimmu.2020.02180
• 发表时间: 2020
• 期刊: Frontiers in immunology
• 影响因子: 7.3
• 作者: Shapiro MR;Yeh WI;Longfield JR;Gallagher J;Infante CM;Wellford S;Posgai AL;Atkinson MA;Campbell-Thompson M;Lieberman SM;Serreze DV;Geurts AM;Chen YG;Brusko TM
• 通讯作者: Brusko TM

Characterization of Type I Interferon-Associated Chemokines and Cytokines in Lacrimal Glands of Nonobese Diabetic Mice.

• DOI: 10.3390/ijms22073767
• 发表时间: 2021-04-05
• 期刊: International journal of molecular sciences
• 影响因子: 5.6
• 作者: Allred MG;Chimenti MS;Ciecko AE;Chen YG;Lieberman SM
• 通讯作者: Lieberman SM

Heterogeneity of Islet-Infiltrating IL-21+ CD4 T Cells in a Mouse Model of Type 1 Diabetes.

1 型糖尿病小鼠模型中胰岛浸润 IL-21 CD4 T 细胞的异质性。

• DOI: 10.4049/jimmunol.2200712
• 发表时间: 2023
• 期刊: Journal of immunology (Baltimore, Md. : 1950)
• 作者: Ciecko,AshleyE;Wang,Yu;Harleston,Stephanie;Drewek,Amber;Serreze,DavidV;Geurts,AronM;Lin,Chien-Wei;Chen,Yi-Guang
• 通讯作者: Chen,Yi-Guang