Differential Regulation of T Cell Responses to the Commensal Bacterium Akkermansia Muciniphila

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Project Summary The intestines are inhabited by a complex community of commensal bacteria known as the microbiota, which play a fundamental role in shaping host physiology and immune function. In general, T cells remain ignorant of commensal bacterial antigens, or adopt a regulatory fate if activated. However, a small number of commensal bacterial antigens have been identified that elicit effector T cell responses. Such commensal- reactive T cells can alter how the immune system responds to local challenges, such as intestinal pathogens. Notably, commensal-reactive T cells have also been shown to influence how the immune system responds in other contexts, such as during autoimmune disease and cancer. This application focuses on the commensal bacterial species Akkermansia muciniphila, which colonizes both healthy mice and humans. The presence of A. muciniphila in the intestines has been linked with changes in host immune function, and protection against a number of disease states, although the mechanisms underlying these effects are unclear. The Barton lab has developed powerful tools for tracking the T cell response to A. muciniphila. They recently used these tools to demonstrate that A. muciniphila induces a unique context-dependent T cell response unlike what has been described for other commensal species. In gnotobiotic mice with a minimal microbiota, A. muciniphila elicits a defined T follicular helper cell response; however, in mice with a more complex SPF microbiota, this bacterium elicits helper T cells with multiple effector phenotypes. These results suggest that the immune response to A. muciniphila is variable and depends on cues other than the presence or absence of the bacteria. Our goal is to understand the mechanisms by which A. muciniphila induces specific types of T cell responses, as well as the implications for host health of altering the anti-commensal immune response. In Aim 1, we will examine the immune response to A. muciniphila in the setting of several defined microbial communities in order to examine how additional commensal species alter the A. muciniphila-specific T cell response. In Aim 2, we will characterize the APCs responsible for presenting A. muciniphila antigens in contexts in which the T cell response to A. muciniphila is varied. Finally, in Aim 3, we will examine how changes in the nature of the A. muciniphila-specific T cell response impact host health. Together, these studies will provide mechanistic insight into how the immune system responds to the microbiota and how immune responses to commensal bacteria can alter host physiology.