TFR cells regulate the specificity of anti-commensal IgA in the gut and repress global IgA responses via IL10

Immunoglobulin A (IgA), the predominant antibody isotype at mucosal surfaces, is regulated by both T cell dependent and T cell independent pathways. Although T follicular regulatory (TFR) cells are known to fine tune humoral responses, their role in microbiota directed IgA regulation has remained unclear. Using a TFR deficient mouse model, we found that oral immunization induced a sustained increase in IgA coated commensal bacteria, expanded the diversity and affinity of IgA targeting, and altered IgA and IgG somatic hypermutation without affecting overall microbial composition or barrier integrity. Mechanistically, TFR cells restrained commensal specific IgA responses through an IL10 dependent, CTLA4 independent pathway, identifying TFR cells as critical gatekeepers of mucosal IgA regulation.