Acquisition of a multifunctional TNFα/iNOS-producing IgA+ plasma cell phenotype in the gut

The largest mucosal surface in the body is in the gastrointestinal (GI) tract, a location that is heavily colonized by normally harmless microbes. A key mechanism required for maintaining a homeostatic balance between this microbial burden and the lymphocytes that densely populate the GI tract is the production and trans-epithelial transport of poly-reactive IgA 1 . Within the mucosal tissues, B cells respond to cytokines, sometimes in the absence of T cell help, undergo class switch recombination (CSR) of their Immunoglobulin (Ig) receptor to IgA, and differentiate to become plasma cells (PC) 2 . However, IgA-secreting PC likely have additional attributes that are needed for coping with the tremendous bacterial load in the GI tract. Here we report that IgA + PC also produce the anti-microbial mediators TNFα and iNOS, and express many molecules that are commonly associated with monocyte/granulocytic cell types. The development of iNOS-producing IgA + PC can be recapitulated in vitro in the presence of gut stroma, and the acquisition of this multi-functional phenotype in vivo and in vitro relies on microbial co-stimulation. Deletion of TNFα and iNOS in B-lineage cells resulted in a reduction in IgA production, altered diversification of the gut microbiota and poor clearance of a gut-tropic pathogen. These findings reveal a novel adaptation to maintaining homeostasis in the gut, and extend the repertoire of protective responses exhibited by some B lineage cells.