Role of DN T cells in colonic microbiota-immune system maturation

项目摘要 “双阴性”(DN)T细胞是一组功能不清的T淋巴细胞，研究较少。初步 数据显示，当GF小鼠被激活时，这些细胞在结肠淋巴组织中特异性地扩增 与健康的人类微生物区系中的特定成员单克隆，尤其是梭杆菌。 这些细胞是肠道T细胞群体中生理上很大的组成部分，约占30% 传统的结肠T细胞，与CD4+和CD8+T细胞的比例相等。尽管如此，他们仍然保持着相对 人们对此知之甚少。DNT细胞扩增的目的以及桑寄生真菌在DNT细胞增殖中的一般作用 健康的微生物区系，目前尚不清楚。我认为桑寄生真菌能培养糖尿病肾病T细胞群。 结肠淋巴组织朝着有助于健康微生物区系成熟的特定功能--免疫 动态平衡。这项建议的目标是探索这些细胞在小鼠肠道系统中的功能。 健康的野生型宿主。在这一探索中将采取两种方法：1)DNT细胞的特征 2)对桑寄生真菌进行生化分级鉴定 哪些特定的微生物成分积极参与了糖尿病肾病T细胞的扩增。这个问题将会得到解决 通过我在免疫生物学和传染病方面的博士专业知识，并通过我的博士后扩展 通过Kasper实验室独特的微生物学、化学和免疫学界面进行微生物组培训。 这项研究解决了目前基础研究的两个未被满足的领域：糖尿病肾病T细胞的生理目的 肠道，以及梭杆菌在健康微生物区系组成中的作用。这两个领域的改进 将有助于扩大目前对宿主免疫-微生物相互作用的理解，并可能提供新的 肠道免疫成分治疗操作的靶点。

Project Summary `Double negative' (DN) T cells are an understudied group of T lymphocytes with unclear function. Preliminary data shows that these cells are specifically expanded in colonic lymphoid tissue when GF mice are monocolonized with specific members of the healthy human microbiota, especially Fusobacterium mortiferum. These cells are a physiologically large component of the intestinal T cell population, constituting ~30% of conventional colonic T cells, equal in proportion to CD4+ and CD8+ T cells. Despite this, they remain relatively poorly understood. The purpose of DN T cell expansion, as well as the general role of F. mortiferum in the healthy microbiota, is currently unknown. I propose that F. mortiferum educates the DN T cell population in the colonic lymphoid tissue towards a specific function that aids in maturation of the healthy microbiota-immune homeostasis. The goal of this proposal is to explore the function of these cells in the intestinal system of healthy wildtype host. Two approaches will be taken in this exploration: 1) characterization of DN T cells expanded in F. mortiferum monocolonization, and 2) biochemical fractionation of F. mortiferum to identify which specific microbial components are actively involved with DN T cell expansion. This will be tackled through my PhD expertise in immunobiology and infectious diseases, and expanded with my postdoctoral training in the microbiome with the Kasper lab's unique interface of microbiology, chemistry, and immunology. This study addresses two current unmet areas of basic research: the physiological purpose of DN T cells in the gut, and the role of Fusobacteria in the composition of healthy microbiota. Improvements in these two areas will help expand current understanding of the host immune-microbial interaction, and may also provide new targets for therapeutic manipulation of the intestinal immune composition.