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

Harvard Medical School, Boston MA

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Abstract

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.