Immune regulation of intestinal health and disease

 描述（由申请人提供）：炎症性肠病（IBD）是一种日益严重的公共卫生和社会经济挑战，影响全球儿科和成人人群。然而，IBD的发病机制知之甚少，治疗选择有限，而且往往无效。基础和转化研究表明，IBD与 针对正常有益的肠道细菌的促炎性CD 4 + T细胞应答的发展。因此，在健康和肠道炎症的背景下，探究限制对肠道细菌的病理性免疫应答的机制对于开发预防和治疗IBD的新疗法至关重要。该实验室和其他实验室的最新研究已经确定了先天淋巴细胞（ILC）群体在调节肠内尼古丁介导的免疫、炎症和组织修复中的作用。在最近发表的和新的初步数据中，我们已经鉴定了第3组ILC（ILC 3）也在通过主要组织相容性复合物II类（MHCII）依赖性相互作用直接限制促炎性大肠杆菌特异性CD 4 + T细胞的发育中起关键作用（赫普沃思et al. Nature，2013和赫普沃思et al.，Science，2015）。重要的是，鼠ILC 3中MHCII的遗传缺失导致T细胞依赖性肠道炎症，并且小儿克罗恩病患者表现出肠道ILC 3上MHCII表达降低。这些发现激发了中心假设，即MHCII+ ILC 3关键地调节对肠道细菌的促炎性CD 4 + T细胞应答，并且对于维持人类胃肠道中的组织稳态是必需的。我们将采用这些强大的基础和翻译方法来描绘ILC 3调节病理性CD 4 + T细胞对肠道细菌和肠道炎症反应的途径。该项目的两个具体目标将确定（i）MHCII+ ILC 3调节病理性大肠杆菌特异性CD 4 + T细胞的细胞和分子机制，以及（ii）在小鼠和人类的健康和炎症肠道中调节ILC 3内在MHCII表达的机制。总的来说，这些研究将系统地询问ILC 3-内在MHCII在基本小鼠模型中的作用和调节，并在健康人类和IBD患者群体中检查这些途径的先驱翻译研究。这些研究将为正在进行的努力提供信息，以开发针对ILC的有效疗法，以预防或治疗儿童和成人的IBD，以及与肠道细菌免疫反应失调相关的多种其他慢性炎症性疾病。

 DESCRIPTION (provided by applicant): Inflammatory bowel disease (IBD) is a growing public health and socio-economic challenge that affects pediatric and adult populations worldwide. However, the pathogenesis of IBD is poorly understood and therapeutic options are limited and often ineffective. Basic and translational studies suggest that IBD is causally-associated with the development of pro-inflammatory CD4+ T cell responses directed against normally beneficial intestinal commensal bacteria. Therefore interrogating the mechanisms that limit pathologic immune responses to commensal bacteria in the context of health and intestinal inflammation will be critical for the development of novel therapeutics to prevent and treat IBD. Recent studies from this and other laboratories have identified a role for populations of innate lymphoid cells (ILCs) in regulating cytokine-mediated immunity, inflammation and tissue repair in the intestine. In recently published and new preliminary data we have identified that group 3 ILCs (ILC3s) also play a critical role in directly limiting the development of pro- inflammatory commensal bacteria-specific CD4+ T cells via major histocompatibility complex class II (MHCII)- dependent interactions (Hepworth et al. Nature, 2013 and Hepworth et al., Science, 2015). Critically, genetic deletion of MHCII in murine ILC3s results in T cell-dependent intestinal inflammation, and pediatric Crohn's disease patient's exhibit reduced MHCII expression on intestinal ILC3s. These findings provoke the central hypothesis that MHCII+ ILC3s critically regulate pro-inflammatory CD4+ T cell responses to commensal bacteria and are essential to maintain tissue homeostasis in the gastrointestinal tract of humans. We will employ these powerful basic and translational approaches to delineate the pathways by which ILC3s regulate pathologic CD4+ T cell responses to commensal bacteria and intestinal inflammation. Two specific aims of this project will determine (i) the cellular and molecular mechanisms by which MHCII+ ILC3s regulate pathologic commensal bacteria-specific CD4+ T cells, and (ii) what regulates ILC3-intrinsic MHCII expression in the healthy and inflamed intestine of mice and humans. Collectively, these studies will systematically interrogate the role and regulation of ILC3-intrinsic MHCII in basic mouse models, and pioneer translational studies examining these pathways in healthy human and IBD patient populations. These studies will inform ongoing efforts to develop effective therapies targeting ILCs to prevent or treat IBD in both children and adults, in addition to multiple other chronic inflammatory diseases associated with dysregulated immune responses to commensal bacteria.