Antigen receptor signaling and cell death resistance controls intestinal humoral response zonation

Abstract

Immunoglobulin A (IgA), the main antibody isotype found in the intestine, has evolved to maintain the stability of commensal communities, and prevent dysbiosis. In stark contrast to systemic antibody response against pathogens, the generation of IgA against intestinal resident microbes assures the simultaneous binding to multiple and diverse commensal-derived antigens. However, the exact mechanisms by which B cells mount such broadly reactive IgA response to the gut microbiome at the mucosal barrier remain elusive. Here we show surface IgA B cell receptor (BCR) is required to confer enhanced B cell fitness during the germinal center reaction in Peyers patches and to mediate selection of gut-homing plasma cells with higher efficiency. We demonstrate that, upon antigen stimulation, IgA+ BCR drives greater intracellular signaling in mouse and human B cells and as consequence, IgA+ B cells received higher positive selection cues in the germinal center. Mechanistically, in vivo IgA BCR signaling offsets Fas-mediated cell death to rescue low affinity B cell clones and redirects the humoral response to an increased variety of commensal strains at the intestinal interface. Our findings revealed a new mechanism linking tissue-specific antigen receptor signaling with B cell fate and localization of antibody production; and have implications for understanding how intestinal antigen recognition shapes humoral immunity in health and disease.