Tissue-Specific Mechanisms of Regulatory T Cells in the CNS during Autoimmune Encephalomyelitis

项目摘要/摘要 多发性硬化症(MS)和其他自身免疫性疾病构成了主要的医疗负担，耗资125美元。 每年10亿美元。自身免疫性疾病是由免疫调节网络的失效引起的。监管T(Treg) 表达转录因子叉头盒蛋白3(Foxp3)的细胞是这些细胞不可缺少的组成部分 网络。此外，几个研究小组最近的研究表明，Treg细胞也有助于组织修复，在 除了施加免疫抑制之外。在自身免疫性疾病期间，Treg细胞在淋巴中被激活 器官和非淋巴靶组织的家，在那里它们坚持在专门的壁龛中限制炎症 并促进组织修复。我们的总体目标是确定这些Treg细胞利基是如何在中央 神经系统(CNS)在细胞和分子水平上改善自身免疫性神经炎症。直接 细胞行为的可视化通常会带来惊喜、新的假设和后续实验，有助于 更好地了解哺乳动物的免疫系统，以及自身免疫和传染病如何 得到有效治疗。基于我们在细胞水平的双光子(2-P)成像方面的专业知识，以及 在分子水平上，我们将使用实验性自身免疫性脑脊髓炎(EAE)小鼠模型 MS to：1)阐明驱动生存的局部线索、小生境的功能组织和运动行为 2)研究Treg细胞如何选择性地靶向刺激 神经炎。我们的实验方法包括对Piezo1通道进行评估，认为它很有希望 选择性扩增Treg细胞的治疗靶点，这是抑制持续自体炎症的理想策略 在保持免疫系统抵抗新感染的能力的同时做出反应。尽管这项提议是有针对性的 具体地说，在更广泛的背景下，我们的项目将提供有关Treg细胞如何微调的基本见解 组织炎症，从而可以开发更好的Treg修饰疗法来治疗自身免疫性疾病、器官 移植、癌症和传染病。

PROJECT SUMMARY/ABSTRACT Multiple sclerosis (MS) and other autoimmune diseases constitute a major healthcare burden at a cost of >$125 billion per year. Autoimmune disorders arise from a failure of immunoregulatory networks. Regulatory T (Treg) cells expressing transcription factor forkhead box protein 3 (Foxp3) are indispensable components of these networks. Moreover, recent studies from several groups suggest that Treg cells also facilitate tissue repair, in addition to exerting immunosuppression. During autoimmune diseases, Treg cells are activated in lymphoid organs and home to non-lymphoid target tissues where they persist in specialized niches to limit inflammation and facilitate tissue repair. Our overall goal is to determine how these Treg cell niches operate in the central nervous system (CNS) to ameliorate autoimmune neuroinflammation at cellular and molecular levels. Direct visualization of cell behavior often leads to surprises, new hypotheses, and follow-up experiments contributing to a better understanding of the mammalian immune system, and how autoimmunity and infectious diseases can be effectively treated. Building on our expertise in two-photon (2-P) imaging at the cellular level, and Ca2+ signaling at the molecular level, we will use the experimental autoimmune encephalomyelitis (EAE) mouse model of MS to: 1) elucidate the local cues that drive survival, functional organization in niches, and motility behaviors of Treg cells in the spinal cord; 2) investigate how Treg cells selectively target processes that incite neuroinflammation. Our experimental approach includes evaluation of the Piezo1 channels as promising therapeutic targets to selectively expand Treg cells, an ideal strategy to curb ongoing autoinflammatory responses while preserving the immune system’s ability to fight new infections. Although this proposal is targeted specifically to MS, in a broader context our project will provide fundamental insights into how Treg cells fine-tune tissue inflammation so that better Treg-modifying therapies can be developed for autoimmune disorders, organ transplantation, cancer, and infectious diseases.