Defining mechanisms of CD8 T cell exhaustion in T1D

定义 T1D 中 CD8 T 细胞耗竭的机制

• 批准号: 9887861
• 负责人: S Alice Long
• 金额: $ 54.42万
• 依托单位: BENAROYA RESEARCH INST AT VIRGINIA MASON
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-10 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9887861
• 关键词: ATAC-seq; Address; Affect; American; Antigens; Autoimmune Diseases; Beta Cell; Biological Models; CD3 Antigens; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; CD8B1 gene; Cells; Cellular Assay; Chronic; Clinical; Cytometry; Data; Defect; Development; Diabetes autoantibodies; Disease; Disease Progression; Epigenetic Process; Exhibits; Favorable Clinical Outcome; Foundations; Frequencies; Funding; Genetic Transcription; Goals; Heterogeneity; Human; IL2 gene; Immune; Immunologic Factors; Immunology; In Vitro; Inflammation; Insulin; Insulin-Dependent Diabetes Mellitus; Interleukin-12; Interleukin-15; Interleukin-2; Knowledge; Lead; Ligation; Link; Longitudinal cohort; Malignant Neoplasms; Manuscripts; Metabolic; Molecular; Outcome; Pathway interactions; Patients; Phenotype; Pilot Projects; Play; Population; Process; Production; Publishing; Receptor Activation; Role; Sampling; Science; Seminal; Signal Pathway; Signal Transduction; Source; System; T-Cell Receptor; T-Lymphocyte; Testing; Therapeutic; Viral; Virus Diseases; Work; base; cell type; chronic infection; cohort; disease heterogeneity; exhaust; exhaustion; improved; innovation; insulin dependent diabetes mellitus onset; islet; novel therapeutics; pre-clinical; prevent; receptor; receptor expression; response; therapy design/development; therapy development; transcription factor; transcriptome sequencing

PROJECT SUMMARY/ABSTRACT A critical barrier to treating Type 1 Diabetes (T1D), an autoimmune disease in which the islet beta cells are destroyed by immune cells, is understanding the heterogeneity of disease. One source of immune heterogeneity recently identified across recent onset T1D subjects is the presence of partially exhausted CD8 T cells in subjects with beneficial response to anti-CD3 therapy (Long, et.al Science Immunology). Likewise, subjects with slower disease progression have great frequencies of islet-specific CD8 T cells with more features of exhaustion. Yet, the mechanisms underlying exhaustion in T1D are not well understood. By contrast, in chronic viral settings it is well established that the IL-2/IL-15 axis is involved in differentiation and persistence and CD8 exhaustion: increased IL-2 availability prevents differentiation, while response to IL-2/IL- 15 is required for persistence. In T1D, we published seminal studies along with others that link alterations in the IL-2/IL-15 axis with T1D. Here, we find that T1D subjects with lower frequencies of exhausted CD8 T cells have higher levels of CD4 IL-2 production and lower levels of IL-15 response in CD8 exhausted cells. Thus, IL- 2/IL-15 defects associated with T1D present a unique opportunity to elucidate the role of IL-2 on CD8 exhaustion. We hypothesize that alterations in the IL-2/IL-15 axis in T1D lead to decreased differentiation into islet-specific exhausted CD8 T cells and reduced persistence. We will test this hypothesis in two focused aims using samples from well curated human cohorts of established T1D, pre- clinical T1D and healthy control (HC) subjects, and multi-dimensional single cell approaches including mass cytometry (CyTOF), RNA-seq and ATAC-seq combined with innovative systems immunology approaches. In Aim 1, we propose to elucidate mechanisms of increased CD4 IL2 production that lead to reduced exhaustion at different stages of disease. In Aim 2, we will elucidate mechanisms of reduced IL-12/IL-15 response in exhausted CD8 T cells that results in limited persistence of exhaustion. Successful completion of these aims will 1) advance our understanding of CD8 T cell exhaustion as an understudied form of tolerance in T1D, 2) improve our understanding of immune factors contributing to T1D disease progression, and 3) provide the foundation for the development of therapies designed to promote exhaustion.

项目摘要/摘要 治疗1型糖尿病（T1D）的关键障碍，这是一种自身免疫性疾病，其中胰岛β细胞为 被免疫细胞破坏的是了解疾病的异质性。免疫的来源 最近在最近发作T1D受试者中发现的异质性是部分耗尽的CD8的存在 对抗CD3疗法有益反应的受试者的T细胞（长期为et.Al Science免疫学）。同样地， 疾病进展较慢的受试者的胰岛特异性CD8 T细胞的频率很高 疲惫的特征。然而，T1D中疲惫的基础机制尚不清楚。经过 对比，在慢性病毒环境中，可以很好地确定IL-2/IL-15轴参与分化和 持久性和CD8疲惫：IL-2的可用性增加可防止分化，而对IL-2/IL-的反应 持久性需要15。在T1D中，我们与其他人一起发表了开创性研究，以联系 带有T1D的IL-2/IL-15轴。在这里，我们发现耗尽的CD8 T细胞频率较低的T1D受试者 在CD8耗尽的细胞中，CD4 IL-2产生水平较高，IL-15反应水平较低。因此，il- 与T1D相关的2/IL-15缺陷为阐明IL-2在CD8上的作用提供了独特的机会 精疲力尽。我们假设T1D中IL-2/IL-15轴的变化导致下降 分化为特异性耗尽的CD8 T细胞并降低持久性。我们将测试这个 使用精心策划的人类同类群体的样本的两个重点目的的假设 临床T1D和健康对照（HC）受试者以及包括质量的多维单细胞方法 细胞仪（细胞仪），RNA-SEQ和ATAC-SEQ结合了创新的系统免疫学方法。在 AIM 1，我们建议阐明CD4 IL2产生增加的机制，从而减少衰竭 在疾病的不同阶段。在AIM 2中，我们将阐明IL-12/IL-15响应降低的机制 耗尽的CD8 T细胞导致疲惫的持久性有限。这些目标成功完成 1）将我们对CD8 T细胞耗尽的理解作为T1D中的一种研究的耐受性形式，2） 提高我们对导致T1D疾病进展的免疫因素的理解，3）提供 开发旨在促进疲劳的疗法的基础。