Tolerogenic and pathologic interactions between ILCs and T cells in autoimmunity

项目摘要 自身免疫和慢性炎性疾病的发展是遗传、免疫和免疫系统的复杂相互作用的结果， 环境和生活方式因素，这是每个人独特的。然而，这些疾病表现为 常见的免疫反应，定义为对自身组织、环境 抗原或肠道微生物。值得注意的是，最近的遗传和实验证据表明， 产生IL-17的CD 4辅助性T（Th 17）细胞是一种主要的致病性细胞类型，其参与了免疫缺陷综合征的发病机制。 炎症性肠病（IBD）、多发性硬化（MS）和类风湿性关节炎（RA）。尽管有这些 尽管有这些进展，但人们仍然对Th 17细胞如何在肿瘤的背景下被诱导和调节知之甚少。 自身免疫最近，我的实验室确定了一种与先天免疫系统相关的细胞类型， 称为第3组先天性淋巴样细胞（ILC 3），通过抑制免疫耐受性而在肠中发挥重要的致耐受性作用。 Th 17细胞通过主要组织相容性复合体抗原提呈对大肠杆菌的应答 II类（MHCII+ ILC 3）。在为该提案生成的新的初步数据中，我现在定义MHCII+ ILC 3 在功能上影响实验性自身免疫性脑脊髓炎（EAE）的进展， T细胞介导的人多发性硬化症（MS），并进一步测试我们是否可以使用这种致耐受性 预防EAE的途径。本研究提案的基本重点是更好地定义ILC 3/T细胞如何 发生相互作用并在功能上影响自身免疫对自身抗原的进展。预计在 该建议的两个目标的结果将决定性地定义调节的作用和治疗潜力。 ILC 3和CD 4 T细胞之间的相互作用在MS的背景下，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.