TFR Cells Suppress Gut Commensal-Specific IgA Via IL-10

Abstract

Immunoglobulin A (IgA) is the predominant antibody (Ab) at mucosal surfaces, playing a critical role in intestinal defense and regulation of gut commensals. A large amount of IgAcoated gut commensals is generated via T cell-independent pathways. However, highaffinity, antigen-specific IgA Abs are produced through T cell help in the germinal centers of gut-associated lymphoid tissues. Through this pathway, T follicular helper (TFH) cells drive affinity maturation by selecting B cells that produce high-affinity Abs, including IgA. Concurrently, T follicular regulatory (TFR) cells, derived from regulatory T cells (Tregs), also regulate this process. TFR cells suppress or enhance Ab responses depending on the context, but their role in gut IgA responses remains unclear. Based on our preliminary data, we hypothesized that TFR cells regulate high-affinity IgA responses through Treg-derived suppressive pathways such as IL-10. To test this, we employed a food allergy model by priming WT controls (Foxp3Cre) and TFR-deficient (Foxp3Cre.Bcl6fl/fl; Bcl6FC) mice with peanut or ovalbumin plus cholera toxin to induce food allergy, collected fecal samples, measured fecal IgA-bound bacteria, and sorted IgA-bound/unbound bacteria for performing 16S sequencing. Additionally, we used adoptive transfer experiments and direct IgA binding assays to probe mechanisms by which TFR cells suppress commensalspecific IgA. We found that Bcl6FC mice exhibited a sustained increase in IgA-coated bacteria following food allergy induction, along with increased abundance of Clostridia, Prevotellaceae, and Desulfovibrionaceae members in the IgA+ fraction. Adoptive transfer of WT TFR cells into Bcl6FC mice restored IgA coating levels to those observed in WT controls. Next, transfer of IL-10-deficient TFR cells failed to suppress the elevated IgA coating observed in Bcl6FC mice, whereas CTLA-4-deficient TFR cells retained this suppressive capacity. Our findings elucidate how anti-commensal IgA is regulated in the gut, with broad implications for immune-mediated conditions including food allergies, autoimmunity, cancer and vaccine development.