Immune regulation of intestinal health and disease

 描述(由申请人提供)：炎症性肠病(IBD)是一个日益严重的公共卫生和社会经济挑战，影响着全世界的儿科和成人人口。然而，IBD的发病机制知之甚少，治疗选择有限，而且往往无效。基础研究和翻译研究表明，IBD与 针对正常有益的肠道共生菌的促炎CD4+T细胞反应的发展。因此，在健康和肠道炎症的背景下，询问限制共生细菌的病理免疫反应的机制对于开发预防和治疗IBD的新疗法至关重要。最近来自该实验室和其他实验室的研究已经确定了固有淋巴样细胞(ILCs)群体在调节细胞因子介导的免疫、炎症和肠道组织修复中的作用。在最近发表的和新的初步数据中，我们发现第3组ILC(ILC3)也通过主要组织相容性复合体II(MHCII)依赖的相互作用在直接限制促炎共生细菌特异性CD4+T细胞的发展中发挥关键作用(Hepworth等人)。《自然》，2013和赫普沃思等人，《科学》，2015)。关键是，小鼠ILC3s中MHCII基因缺失会导致T细胞依赖性肠炎，儿童克罗恩病患者的肠道ILC3s上MHCII表达减少。这些发现提出了一个中心假设，即MHCII+ILC3s关键地调节促炎的CD4+T细胞对共生菌的反应，并且对于维持人类胃肠道的组织内稳态是必不可少的。我们将使用这些强大的基本和翻译方法来描述ILC3调节病理性CD4+T细胞对共生菌和肠道炎症的反应的途径。该项目的两个具体目标将确定(I)MHCII+ILC3调节病理性共生细菌特异的CD4+T细胞的细胞和分子机制，以及(Ii)在健康和炎症的小鼠和人的肠道中调节ILC3固有的MHCII表达的因素。总而言之，这些研究将系统地询问ILC3固有的MHCII在基本小鼠模型中的作用和调控，并在健康人和IBD患者群体中研究这些途径的先驱翻译研究。这些研究将为正在进行的针对ILC的有效疗法的开发提供信息，以预防或治疗儿童和成人的IBD，以及与共生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.