B cells regulate T cell transfer colitis by partially reconstituting luminal IgA and modulating the colonic microbiota.

Abstract

Loss of immune tolerance to commensal microbial antigens is a central driver of inflammatory bowel disease. While regulatory T cells are well recognized in maintaining intestinal homeostasis, the contribution of B cells-particularly IgA-secreting cells-remains incompletely defined. In the T cell transfer colitis model, cotransfer of splenic B cells attenuates disease, an effect largely attributed to IL-10-producing regulatory B cells (Bregs). However, alternative B cell-dependent mechanisms have not been fully explored. Here, we investigated whether splenic B cells regulate T cell transfer colitis through IgA-dependent mechanisms independent of Breg-associated cytokines. We show that splenic B cells from wild-type C57BL/6 (B6) mice reconstitute bone marrow and peripheral B cell compartments in RAG1⁻/⁻ recipients, undergo class switching, migrate to the colonic lamina propria as sIgA⁺ B lineage cells, and partially restore luminal secretory IgA. B cell cotransfer significantly attenuated clinical and histological colitis without increased expression of canonical Breg-associated cytokines, including interleukin-10, transforming growth factor β, and interleukin-35 subunits. In contrast, splenic B cells from IgA-deficient mice failed to attenuate colitis despite comparable peripheral B cell reconstitution. Restoration of secretory IgA was associated with increased bacterial IgA coating, reduced fecal bacterial burden, and remodeling of the colonic microbiota, including enrichment of beneficial commensal taxa. Importantly, because IgA-deficient B cells failed to attenuate colitis despite comparable peripheral B cell reconstitution, these findings support an important role for IgA in mediating the protective effect of B cell transfer. Collectively, these findings identify IgA-mediated modulation of the microbiota as an alternate mechanism by which B cells attenuate T cell transfer colitis, highlighting a Breg-independent regulatory pathway with potential relevance to inflammatory bowel disease pathogenesis.