Unraveling the interactions between T regulatory cells and the gut microbiota in

描述(由申请者提供)：肠道中有数万亿与免疫系统保持平衡的微生物。这种关系的中断，无论是由于不适当的免疫细胞激活或微生物组的变化，都可能导致慢性肠炎，并进展为炎症性肠病。微生物区系对系统和粘膜免疫系统的正常发育也是必不可少的，因为没有微生物的小鼠在先天性和获得性免疫细胞的发育和功能方面存在重大缺陷。T调节细胞(Tregs)通过控制炎症反应，在维持肠道内环境平衡方面发挥重要作用，从而促进宿主-微生物区系共存。虽然最近的研究已经确定了影响Treg发育的特定微生物种类，但对Treg如何影响肠道微生物群落动态知之甚少。这项建议的目的是确定Treg对肠道微生物区系成员和功能的贡献，确定Treg影响微生物区系动态的机制，并描述微生物区系对Treg细胞持久性、功能和稳定性的影响。这些研究将结合经典的微生物学、免疫学和计算生物学方法。这一提议将提供关于Treg如何影响微生物区系以促进肠道内稳态的健康状态的见解，以及微生物区系的扰动如何影响Treg细胞的发育、功能和可塑性。肠道微生物区系组成的变化与炎症性肠病、1型糖尿病和肥胖症的发展有关。因此，了解免疫系统的变化如何影响微生物群落动态，对于开发有效的免疫疗法具有重要意义。这项研究中提出的实验可能会为Treg如何影响肠道微生物区系提供关键的见解，这不仅对于基于Treg的免疫疗法的开发和炎症性肠病，而且对于了解抗生素暴露对人类健康的后果都是重要的。

DESCRIPTION (provided by applicant): The gut harbors trillions of microbes that live in equilibrium with the immune system. Disruption in this relationship, either by improper immune cell activation or changes in the microbiome, can result in chronic intestinal inflammation with progression to inflammatory bowel disease. The microbiota is also essential for the proper development of both the systemic and mucosal immune systems, as mice devoid of microbes have significant defects in innate and adaptive immune cell development and function. T regulatory cells (Tregs) play a critical role in maintaining gut homeostasis by controlling inflammatory responses and thus fostering host-microbiota co-existence. While recent studies have identified specific microbial species that influence Treg development, very little is known about how Tregs affect gut microbial community dynamics. The aims of this proposal are to define the contribution of Tregs to gut microbiota membership and function, determine the mechanism by which Tregs affect microbiota dynamics, and delineate the microbiota's effects on Treg cell persistence, function and stability. These studies will combine classic microbiology, immunology and computational biology approaches. This proposal will provide insights into how Tregs affect the microbiota to promote healthy states of gut homeostasis, as well as how perturbation of the microbiota affects Treg cell development, function and plasticity. Changes in the composition of the gut microbiota have been linked to the development of inflammatory bowel disease, type 1 diabetes and obesity. Therefore understanding how alterations in the immune system affect microbial community dynamics is of great interest for developing effective immunotherapies. The experiments proposed in this study may provide critical insight into how Tregs affect the gut microbiota, which will be important not only for the development of Treg-based immunotherapies and inflammatory bowel disease, but also for understanding the consequences of antibiotics exposure for human health.