Saturday, November 23, 2024
11/23/2024
PROJECT ABSTRACT The gastrointestinal tract is colonized with trillions of normally beneficial microbes, termed the microbiota, that are essential for human health. However, the pathogenesis of numerous infectious, inflammatory, and metabolic diseases involves a loss of immunologic tolerance to the gut microbiota. This has been demonstrated robustly in basic, translational, and clinical studies of inflammatory bowel disease (IBD). The fundamental focus of our proposed renewal for R01AI123368 is to build on recent paradigm-shifting results from the first funding cycle that detailed a novel pathway that is essential to orchestrate immune tolerance to gut microbiota and restrain intestinal inflammation. Specifically, our prior studies detailed how group 3 innate lymphoid cells (ILC3s) present microbiota-derived antigens to CD4 T cells on MHCII, instruct the differentiation of a unique form of RORgt+ regulatory T cells (Tregs), and prevent spontaneous intestinal inflammation. Further, we find that these cellular interactions are dysregulated in the inflamed intestine of individuals with IBD (see Zhou et al., Nature, 2022 and Lyu et al., Nature, 2022 as the most recent examples). We generated new preliminary data to support this renewal application where we propose to mechanistically advance this paradigm and will explore the therapeutic potential of our key findings. This includes three specific aims, which will: (i) define how ILC3s sense microbiota to initiative antigen presentation, (ii) elucidate key molecular determinants endowing a tolerogenic program in MHCII+ ILC3s, and (iii) identify whether MHCII+ ILC3s can be harnessed to enforce tolerance to diverse microbes or restrain gut inflammation as a pre-clinical therapy. We will employ basic mouse models, as well as translate our findings into human specimens. This research is directly relevant to IBD and many other chronic inflammatory diseases where disruptions to immune tolerance underlie disease pathogenesis, and it is expected that our mechanistic results will provoke new opportunities for preventative, therapeutic or curative treatment strategies.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).
