Tolerogenic and pathologic interactions between ILCs and T cells in autoimmunity

项目总结 自身免疫和慢性炎症性疾病的发生是遗传、 每个人都有独特的环境和生活方式因素。然而，这些疾病表现为 常见的免疫学反应，定义为对自身组织、环境的持续高反应性 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 产生IL-17的CD4T辅助细胞(Th17)是一种主要的致病细胞类型，参与了慢性粒细胞白血病的发病机制。 炎症性肠病(IBD)、多发性硬化症(MS)和类风湿性关节炎(RA)。尽管如此 随着研究的深入，Th17细胞是如何被诱导和调控的，目前还不清楚。 自身免疫力。最近我的宿主实验室确定了一种相关的细胞类型的先天免疫系统， 被称为第3组固有淋巴样细胞(ILC3)，通过抑制在肠道中发挥重要的耐受作用 Th17细胞通过主要组织相容性复合体提呈抗原对共生菌的应答 第二类(MHCII+ILC3)。在为该提案生成新初步数据中，我现在定义MHCII+ILC3 功能性影响实验性自身免疫性脑脊髓炎(EAE)进展的动物模型 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利用这种耐受性 预防EAE的途径。这项研究提案的基本焦点是更好地定义ILC3/T细胞如何 相互作用发生并在功能上影响自身免疫向自身抗原的发展。预计 这项提议的两个目标的结果将关键地定义调节的作用和治疗潜力 多发性硬化症中ILC3和CD4T细胞之间的相互作用可以扩展到其他形式的T细胞 细胞介导的自身免疫。

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.