Cytokine regulation of mucosal inflammation

PROJECT ABSTRACT Uncontrolled inflammation in the gastrointestinal tract underlies the pathogenesis and progression of multiple chronic human diseases including allergy, hypersensitivity, inflammatory bowel disease (IBD), and graft- versus-host-disease (GVHD), and there is an urgent need to develop novel approaches to prevent, limit or reverse gut inflammation. The fundamental focus of our proposed renewal for R01AI145989 is to build on recent paradigm-shifting results from the first funding cycle defining that tissue resident lymphocytes shape the protective versus pathologic outcomes of key cytokines in gastrointestinal inflammation. Specifically, our prior studies detailed how group 3 innate lymphoid cells (ILC3s) drive immune tolerance and during homeostasis and inflammation by sensing and regulating key cytokine networks. We determined that ILC3s sense IL-23 to upregulate the immunoregulatory molecule, CTLA-4, which critically restrains gut inflammation (Ahmed et al., Nature, 2024). Further, we find that these cellular interactions are dysregulated in the inflamed intestine of individuals with IBD. These surprising data provoke the need to more broadly consider CTLA-4 biology beyond conventional T cells and in the context of distinct cytokine signals or microbial exposures. We generated new preliminary data to support this renewal application where we propose to mechanistically advance this paradigm. This includes two specific aims, which will define how specific tissue- resident innate and innate-like lymphocytes augment different types of immunity and inflammation in the intestine. We expect that our mechanistic results will provoke new opportunities for preventative, therapeutic or curative treatment strategies targeting chronic gut inflammation.