Type 1 IFN in Type 1 Diabetes: Influencing Beta-Cell and CD8+ T cell interactions

1 型糖尿病中的 1 型 IFN：影响 β 细胞和 CD8 T 细胞的相互作用

• 批准号: 9267152
• 负责人: Brittney N Newby
• 金额: $ 3.73万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-05-16 至 2020-05-15
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9267152
• 关键词: Affect; Antigen Presentation; Antigen Presentation Pathway; Antiviral Agents; Autoantibodies; Autoimmune Process; Autoimmunity; Beta Cell; Biological Response Modifiers; Biology; CD8-Positive T-Lymphocytes; Capsid Proteins; Cell Communication; Cell Death; Cell Line; Cell physiology; Cells; Chronic Hepatitis C; Clinical; Complications of Diabetes Mellitus; Cues; Cytoplasmic Granules; Data; Development; Diabetes Mellitus; Disease Progression; Disease model; Effector Cell; Enterovirus; Environment; Environmental Risk Factor; Epidemic; Event; Exocytosis; Family; Foundations; Functional disorder; Future; Genes; Genetic Predisposition to Disease; Goals; Hairy Cell Leukemia; Health Expenditures; Healthcare Systems; Heart Diseases; Histocompatibility Antigens Class I; Human; Hyperglycemia; Immune Tolerance; Immune system; Incidence; Individual; Infection; Innate Immune System; Insulin; Insulin-Dependent Diabetes Mellitus; Interferon-alpha; Interferon-beta; Interferons; Investigation; Islets of Langerhans; Knowledge; Lead; Link; Lymphocyte; MHC Class I Genes; Mediating; Mediator of activation protein; Metabolic Diseases; Molecular; Multiple Sclerosis; Neuropathy; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Organ Donor; PTPN22 gene; Pathogenesis; Pathway interactions; Patients; Peripheral Vascular Diseases; Phenotype; Population; Prevention; Prevention strategy; Production; RNA; Regulation; Reporting; Research; Risk; Role; Signal Pathway; Signal Transduction; Susceptibility Gene; T-Lymphocyte; TYK2; Testing; Tumor Necrosis Factors; United States; Virus; Virus Diseases; adaptive immune response; autoreactivity; clinical care; cost; cytokine; cytotoxic; cytotoxicity; diabetic; experience; genome wide association study; immune activation; immunoregulation; in vitro Model; inflammatory milieu; innovation; insight; insulin dependent diabetes mellitus onset; interferon-alpha B; islet; member; novel marker; novel therapeutic intervention; novel therapeutics; peripheral blood; pleiotropism; public health relevance; response; transcriptome; type I diabetic

 DESCRIPTION (provided by applicant): Although the initial events contributing to the development of Type 1 Diabetes (T1D) remain elusive, mounting evidence supports a crucial role for the innate immune system and environmental factors, such as viruses, in the progression of disease. Further investigation is needed to understand how innate immune activation leads to loss of immunological tolerance and ensuing beta cell destruction by the CD8+ T cell. Therefore, the long- term goal of this research is to understand the causal relationship between genetic susceptibility, precipitating environmental factors, and innate immune mediators in the initiation and progression of T1D. This particular application aims to assess the effect of Type 1 Interferons (T1-IFN) on beta cell and CD8+ T cell interactions in a human in vitro model of T1D. Previous studies have shown that T1-IFN are found in the islets of T1D patients along with increased MHC Class I (MHC-I) expression. However, the underlying molecular mechanisms leading to increased MHC-I within the beta cell have not been well characterized. Also, due to the immunomodulatory effects displayed by T1-IFN, the presence of these cytokines within the diabetic islet may serve to modulate CD8+ T cell responses. The central hypothesis portends that T1-IFN alter the microenvironment of the diabetic islet through regulation of members of the MHC-I antigen processing and presentation pathway and by directly enhancing CTL-mediated beta cell death. This hypothesis will be tested through two specific aims: 1) Determine how T1-IFN regulate MHC-I antigen processing & presentation by beta cells; and 2) Elucidate the impact of T1-IFN on beta cell recognition and destruction by autoreactive CD8+ T cells. In Aim 1, utilizing beta cell lines and primary human islets, mechanistic studies aimed at characterizing the antigen processing and presentation pathway, specifically the immunoproteasome, will be performed. This will be followed by in depth analysis of signaling pathways responsible for inducing these responses in beta cells. Expounding upon preliminary studies, aim 2 will investigate the immunomodulatory effects of T1-IFN in the context of CD8+ T cell cytotoxicity, specifically factors involved in the granule exocytosis pathway and TNF receptor ligand family. Furthermore, T1-IFN mediated signaling pathways important for the acquisition of CD8+ T cell effector function will be analyzed. A majority of the current knowledge regarding T1-IFN biology has been derived using other disease models. This research is innovative in that it seeks to understand existing paradigms in T1-IFN biology in the context of T1D autoimmunity. This research is significant because successful completion of these studies will provide direct evidence as to how T1-IFN modulate beta cell - CD8 T cell interactions and will provide a mechanistic link between environmental factors, immune activation, and T1D pathogenesis. Ultimately, the knowledge gained here will serve as a foundation for future studies examining the functional significance of T1D susceptibility alleles in T1-IFN responsiveness, which may lead to the development of new therapeutic approaches in T1D that specifically target the T1-IFN signaling pathway.

 描述（由申请人提供）：虽然导致1型糖尿病（T1 D）发展的初始事件仍然难以捉摸，但越来越多的证据支持先天免疫系统和环境因素（如病毒）在疾病进展中的关键作用。需要进一步的研究来了解先天免疫激活如何导致免疫耐受的丧失和随后的CD 8 + T细胞对β细胞的破坏。因此，本研究的长期目标是了解遗传易感性、沉淀环境因素和先天免疫介质在T1 D的启动和进展中的因果关系。该特定应用旨在评估1型干扰素（T1-IFN）对T1 D的人体外模型中的β细胞和CD 8 + T细胞相互作用的影响。先前的研究已经表明，T1-IFN在T1 D患者的胰岛中发现沿着增加的MHC I类（MHC-I）表达。然而，导致β细胞内MHC-I增加的潜在分子机制尚未得到很好的表征。此外，由于T1-IFN显示的免疫调节作用，糖尿病胰岛内这些细胞因子的存在可用于调节CD 8 + T细胞应答。中心假设预示T1-IFN通过调节MHC-I抗原加工和呈递途径的成员以及通过直接增强CTL介导的β细胞死亡来改变糖尿病胰岛的微环境。这一假设将通过两个具体目标进行检验：1）确定T1-IFN如何调节β细胞对MHC-I抗原的加工和呈递; 2）阐明T1-IFN对自身反应性CD 8 + T细胞对β细胞识别和破坏的影响。在目标1中，将利用β细胞系和原代人胰岛，进行旨在表征抗原加工和呈递途径（特别是免疫蛋白酶体）的机制研究。 随后将深入分析负责诱导β细胞中这些反应的信号通路。在初步研究的基础上，目的2将研究T1-IFN在CD 8 + T细胞毒性背景下的免疫调节作用，特别是参与颗粒胞吐途径和TNF受体配体家族的因素。此外，T1-IFN介导的信号转导途径的重要收购的CD 8 + T细胞效应功能将进行分析。目前关于T1-IFN生物学的大部分知识是使用其他疾病模型获得的。这项研究是创新的，因为它试图了解现有的范式在T1-IFN生物学的背景下，T1 D自身免疫。这项研究是重要的，因为这些研究的成功完成将提供直接的证据，T1-IFN如何调节β细胞-CD 8 T细胞的相互作用，并将提供环境因素，免疫激活和T1 D发病机制之间的机制联系。最终，这里获得的知识将作为未来研究的基础，研究T1 D易感性等位基因在T1-IFN反应性中的功能意义，这可能会导致开发新的T1 D治疗方法，专门针对T1-IFN信号通路。