In this proposal we will investigate the mechanisms by which an individual commensal bacterial species induces generation of a specific effector CD4 T cell subset in the intestinal lamina propria. Commensal bacteria represent a diverse microbial community that permanently resides in the intestines of all mammals. As a community, commensals are known to affect multiple aspects of host immunity. Perturbations in the composition of this community are important determinants of disease pathogenesis in many autoimmune conditions, e.g. inflammatory bowel diseases (IBD), diabetes, arthritis. However, how individual microbiota members modulate host immunity in order to provide protection or exacerbate disease is unclear, which has impeded identification of participating molecular mechanisms. We identified a commensal, segmented filamentous bacteria (SFB), that can specifically induce Th17 cells in the gut. Th17 cells are pro-inflammatory cells that play important protective roles against bacterial and fungal pathogens while at the same time contribute to autoimmunity, including IBD and colitis, in susceptible hosts. We showed that presence of SFB in mice specifically induces Th17 cells and leads to increase in mucosal protection against intestinal infections and exacerbation of autoimmunity. Presently, SFB are the only known commensal that induces Th17 cells. We propose to identify host cells responsible for detecting SFB and presenting antigens in order to induce Th17 cells. We will examine the role of intestinal dendritic cells (iDCs), which have been implicated in gut Th17 cell induction. We have discovered that genetic ablation of one iDC subset, the CD103+CD11b+ DCs, leads to a decrease in Th17 cells. We will examine whether CD103+CD11b+ DCs are required for SFB-mediated effects in the gut. We will also examine if SFB antigens are directly sampled to induce SFB-specific Th17 cells. We will utilize a collection of genetic models that we have re- derived SFB-free and Th17 cell-free. This will allow us to colonize these models with SFB and assess the role of the corresponding mechanisms specifically in SFB-mediated Th17 cell induction. Understanding the mechanisms by which commensals modulate T cell homeostasis, and in particular Th17 cell induction will allow for the development of therapies to mimic or antagonize such mechanisms for the directional regulation of inflammatory T cell responses for the boost of mucosal protection in the case of intestinal infections or the decrease in inflammation in the case of IBD.
T helper 17 (Th17) cells provide protection against mucosal infections and at the same time have emerged as major contributors to chronic inflammatory conditions, such as inflammatory bowel diseases (IBD). Studies from our laboratory demonstrated that Th17 cells in the gut are induced by commensal bacteria and, specifically, by segmented filamentous bacteria (SFB), however, the mechanisms by which SFB induce Th17 cells have remained unknown. In this proposal we have designed studies to understand how SFB are detected by the host and how they induce Th17 cells, which will provide important targets for modulating Th17 cell numbers in the gut in order to control pathogenic immune responses.
|Goto, Yoshiyuki; Obata, Takashi; Kunisawa, Jun et al. (2014) Innate lymphoid cells regulate intestinal epithelial cell glycosylation. Science 345:1254009|
|Goto, Yoshiyuki; Panea, Casandra; Nakato, Gaku et al. (2014) Segmented filamentous bacteria antigens presented by intestinal dendritic cells drive mucosal Th17 cell differentiation. Immunity 40:594-607|