Tolerogenic and pathologic interactions between ILCs and T cells in autoimmunity

自身免疫中 ILC 和 T 细胞之间的耐受性和病理性相互作用

• 批准号: 10231152
• 负责人: John Benjamin Grigg
• 金额: $ 3.08万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-06 至 2022-02-25
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10231152
• 关键词: Active Immunization; Adoptive Transfer; Affect; Anatomy; Animal Model; Anti-Inflammatory Agents; Antigen Presentation; Antigen-Presenting Cells; Antigens; Apoptosis; Autoantigens; Autoimmune; Autoimmune Diseases; Autoimmunity; CD4 Positive T Lymphocytes; CD80 gene; CD86 gene; Cell Communication; Cell Count; Cells; Central Nervous System Diseases; Chronic; Clinical; Complex; Data; Disease; Economic Burden; Environmental Risk Factor; Experimental Autoimmune Encephalomyelitis; Gene Expression Profile; Genetic; Genetic Models; Histocompatibility Antigens Class II; Human; Immune; Immune response; Incidence; Individual; Infection; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Innate Immune System; Interleukin-17; Intestines; Laboratories; Lead; Life Style; Location; Lymphoid Cell; Mediating; Multiple Sclerosis; Mus; Myelin; Neoplasms; Neuraxis; Pathogenesis; Pathogenicity; Pathologic; Pathway interactions; Peptides; Peripheral; Physiologic pulse; Play; Predisposition; Prevention; Public Health; Publications; Research Proposals; Rheumatoid Arthritis; Role; T cell response; T-Lymphocyte; Testing; Therapeutic; Tissues; autoreactivity; cell type; chronic inflammatory disease; commensal bacteria; differential expression; experimental study; gain of function; in vivo; inflammatory disease of the intestine; lifestyle factors; loss of function; lymph nodes; microorganism; mouse model; neuropathology; novel; prevent; response; side effect; systemic autoimmune disease

PROJECT SUMMARY Autoimmunity and chronic inflammatory diseases develop as a result of a complex interplay of genetic, environmental, and lifestyle factors that are unique to each individual. However, these diseases manifest in a common immunologic response defined by a persistent hyper-responsiveness to self-tissues, environmental antigens, or commensal microorganisms. Notably, recent genetic and experimental evidence demonstrate that IL-17 producing CD4 T helper (Th17) cells are a major pathogenic cell type involved in the pathogenesis of inflammatory bowel disease (IBD), multiple sclerosis (MS), and rheumatoid arthritis (RA). Despite these advances, it remains poorly understood how Th17 cells are induced and regulated in the context of autoimmunity. Recently my host laboratory defined that a related cell type of the innate immune system, termed group 3 innate lymphoid cells (ILC3), play an essential tolerogenic role in the intestine by restraining Th17 cell responses to commensal bacteria through antigen-presentation via major histocompatibility complex class II (MHCII+ ILC3). In new preliminary data generated for this proposal, I now define that MHCII+ ILC3 functionally impact the progression of experimental autoimmune encephalomyelitis (EAE), an animal model for T-cell mediated human multiple sclerosis (MS), and further test whether we can employ this tolerogenic pathway to prevent EAE. The fundamental focus of this research proposal is to better define how ILC3/T cell interactions occur and functionally impact the progression of autoimmunity to self-antigens. It is expected that results from the two aims of this proposal will crucially define the role and therapeutic potential of modulating interactions between ILC3s and CD4 T cells in the context of MS that could be extended to other forms of T cell mediated autoimmunity.

项目摘要 自身免疫性和慢性炎症性疾病由于遗传的复杂相互作用而出现 每个人独有的环境和生活方式因素。但是，这些疾病表现在 常见的免疫反应由对自我组织的持续性超反应来定义 抗原或共生微生物。值得注意的是，最近的遗传和实验证据表明 IL-17产生CD4 T辅助器（TH17）细胞是参与参与的主要致病细胞类型 炎症性肠病（IBD），多发性硬化症（MS）和类风湿关节炎（RA）。尽管如此 进步，它仍然很了解如何在 自身免疫性。最近，我的宿主实验室定义了先天免疫系统的相关细胞类型， 称为3组先天淋巴样细胞（ILC3），通过限制在肠中起着重要的耐受作用 Th17细胞通过主要组织相容性复合物通过抗原呈递对共生细菌的反应 II类（MHCII+ ILC3）。在该提案生成的新初步数据中，我现在定义MHCII+ ILC3 在功能上影响实验自身免疫性脑脊髓炎（EAE）的进展，一种动物模型 T细胞介导的人类多发性硬化症（MS），并进一步测试我们是否可以采用这种耐受性 防止EAE的途径。该研究建议的基本重点是更好地定义ILC3/T细胞的方式 发生相互作用并在功能上影响自身免疫对自我抗原的发展。预计 该提案的两个目标的结果将至关重要地定义调节的作用和治疗潜力 在MS的背景下，ILC3S和CD4 T细胞之间的相互作用可以扩展到其他形式的T 细胞介导的自身免疫。