Integrin β7 sustains ileal humoral immunity and microbial biogeography during chronic TNF-driven ileitis

Integrin α4β7 directs lymphocyte trafficking to the intestinal lamina propria (LP) and is a major therapeutic target in inflammatory bowel disease (IBD). Although integrin (Itg) β7 has been extensively studied in T-cell recruitment, its role in protective mucosal humoral immunity during chronic ileitis remains unclear. To investigate the role of itg β7 in intestinal immune compartmentalization, we crossed TNFΔARE mice, which develop Crohn's-like ileocolitis with Itg β7-deficient mice. Intestinal inflammation, lymphocyte trafficking, ileal LP immune cell composition, IgA responses, and microbial community structure were assessed using histopathology, competitive homing assays, flow cytometry, mass cytometry, ELISA, and 16S rRNA gene sequencing. β7 deficiency exacerbated TNF-driven ileitis in an age-dependent manner. Competitive homing assays demonstrated early impaired recruitment of β7-deficient lymphocytes to the ileal LP. This defect resulted in a selective reduction of intestinal B cells and antibody secreting cells (ASC), whereas T-cell migration to ileum remained largely preserved, indicating differential reliance of lymphocyte subsets on β7-mediated trafficking. Mass cytometry analysis of ileal leukocytes showed enrichment of α4β7 expression on B cells and ASC, providing a mechanistic basis for their selective dependence on β7. Consistent with impaired mucosal humoral immunity, β7-deficient mice exhibited significantly reduced fecal and serum IgA levels, associated with altered microbial community structure and disruption of normal mucosal-luminal microbial biogeography, with partial overlap with microbial community changes observed in IgA-deficient mice. These findings identify β7 integrin as a non-redundant regulator of ileal mucosal humoral immunity during chronic TNF-driven ileitis. Beyond its established role in T cell trafficking, β7 sustains B-cell recruitment, IgA production, and microbial organization in the inflamed ileum, thereby limiting ileitis severity, although additional β7-dependent immune compartments, including αEβ7-associated intraepithelial lymphocyte populations, may also contribute to disease regulation.