Regulation of host-commensal relationships in human health and disease

描述（由申请人提供）：人体免疫系统对于防止病原微生物感染至关重要。然而，针对我们自身组织的不适当的免疫反应或无害的环境触发因素，如我们周围的有益细菌，可以促进自身免疫或慢性炎症性疾病。事实上，在患者和鼠模型系统中的新兴研究表明，异常的宿主-宿主关系与许多慢性炎性疾病（例如炎性肠病（IBD））相关或因果联系。遗传关联和流行病学研究表明，IBD与先天性和适应性免疫应答失调有关，这些免疫应答促进宿主-宿主相互作用失调和宿主细菌驱动的慢性肠道炎症。最近的研究强调了先天性淋巴细胞（ILC）及其效应细胞因子IL-22在调节肠道炎症中的作用。在新的初步研究中，我发现ILC对于通过解剖学上将肠道细菌的限定子集限制于健康哺乳动物的肠道相关淋巴组织（GALT）来维持选择性宿主-肠道关系至关重要。这种选择性调节可以通过两种机制发生;首先，IL-22细胞因子产生的先天途径限制GALT驻留的肠道细菌的外周传播以防止全身性炎症。其次，ILC直接调节适应性免疫应答，并维持正常的宿主对GALT驻留的肠道细菌的免疫应答，以防止肠道炎症。最后，我还观察到来自健康人类供体的肠道样品中ILC的存在，以及IBD患者中与相同定义的GALT驻留肠道细菌子集的失调的宿主-肠道关系。我将采用这些强大的基础和翻译方法来描绘调节宿主-宿主关系和维持人类健康和IBD背景下肠道内稳态的途径。本项目的三个具体目标将确定（i）ILC调节选择性宿主-宿主关系以维持全身免疫细胞稳态的先天机制，（ii）ILC调节宿主适应性免疫应答并维持宿主-宿主关系以预防肠道炎症的机制，和（i）调节先天和适应性宿主-宿主关系的途径是否失调并与人IBD的疾病严重程度相关。总的来说，这些研究将系统地询问ILC在基本小鼠模型中维持正常宿主-宿主关系的作用和机制，并在人类患者中研究这些途径的先驱翻译研究。我预计，定义ILC调节选择性宿主-宿主关系的机制贡献可以确定新的靶点，并指导IBD和多种其他慢性人类炎症性疾病的未来预防和治疗策略的发展。

DESCRIPTION (provided by applicant): The human immune system is critical to protect against infection with pathogenic microorganisms. However, inappropriate immune responses against our own tissues or non-harmful environmental triggers such as beneficial commensal bacteria that surround us can promote autoimmune or chronic inflammatory diseases. Indeed, emerging studies in patients and murine model systems indicate that abnormal host-commensal relationships are either associated with or causally linked to numerous chronic inflammatory diseases, such as inflammatory bowel disease (IBD). Genetic association and epidemiologic studies suggest that IBD is associated with dysregulated innate and adaptive immune responses that promote dysregulated host- commensal interactions and commensal bacteria-driven chronic intestinal inflammation. Recent studies have highlighted a role for innate lymphoid cells (ILCs) and their effector cytokine IL-22 in regulating intestinal inflammation. In new preliminary studies, I identified that ILCs are critical for maintenance of selective host- commensal relationships by anatomically-restricting a defined subset of commensal bacteria to the gut associated lymphoid tissues (GALT) of healthy mammals. This selective regulation could occur via two mechanisms; first, an innate pathway of IL-22 cytokine production limited peripheral dissemination of GALT- resident commensal bacteria to prevent systemic inflammation. Second, ILCs directly regulated adaptive immune responses and maintained normal host immune responses to GALT-resident commensal bacteria to prevent intestinal inflammation. Finally, I also observed the presence of ILCs in intestinal samples from healthy human donors, and dysregulated host-commensal relationships to the same defined subset of GALT- resident commensal bacteria in IBD patients. I will employ these powerful basic and translational approaches to delineate the pathways that regulate host-commensal relationships and maintain intestinal homeostasis in the context of human health and IBD. Three specific aims of this project will determine (i) the innate mechanism by which ILCs regulate selective host-commensal relationships to maintain systemic immune cell homeostasis, (ii) mechanisms by which ILCs regulate host adaptive immune responses and maintain host- commensal relationships to prevent intestinal inflammation, and (i) whether the pathways regulating innate and adaptive host-commensal relationships are dysregulated and associated with disease severity in human IBD. Collectively, these studies will systematically interrogate the role and mechanisms by which ILCs maintain normal host-commensal relationships in basic mouse models and pioneer translational studies examining these pathways in human patients. I anticipate that defining the mechanistic contributions of ILCs to regulating selective host-commensal relationships could identify novel targets and direct the development of future preventative and therapeutic strategies to IBD and multiple other chronic human inflammatory diseases.