Tuesday, April 29, 2025
4/29/2025
Regulation of TLR signaling in anti-commensal B cell responses and mucosal inflammation - Project Summary Mucosal surfaces house numerous commensal and symbiotic bacteria, viruses and other microorganisms, which establish mutually beneficial interactions with their host. This microbial colonization relies on complex interactions with the innate and adaptive immune systems, including the generation of antibodies against commensal bacteria antigens. There is a pressing need to understand how adaptive immune responses to commensals are regulated, and how failure of these mechanisms lead to inflammation and immune pathology. Recent studies have identified a requirement for toll-like receptor (TLR) signaling in B cells in generating anti- commensal antibodies. We have previously shown that the cell surface receptor integrin αvβ3 and components of the autophagy pathway regulate TLR signaling in B cells to prevent overexpansion of autoreactive cells and autoimmunity. In preliminary studies, we have shown that B cell-specific αv-knockout mice (αv-CD19 mice) have increase numbers of spontaneous germinal centers in the intestine and are more susceptible to inflammatory colitis. Based on these data, we hypothesize that αvβ3 regulates B cell responses to commensal bacteria to maintain defense against infection but prevent overactive inflammatory responses. In this application we propose to test this hypothesis by: (1) measuring anti-commensal antibodies and repertoires in αv-CD19 and control mice, and following B cell responses after bacterial colonization; (2) determining the mechanism of increased susceptibility to DSS colitis in αv-CD19 mice. This research is highly significant as it will provide important insights into mechanisms of regulation of anti-commensal antibody responses, and if successful, will establish a new paradigm linking dysregulated TLR signaling in B cells to susceptibility to colitis.
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