Acquisition of a multifunctional IgA+ plasma cell phenotype in the gut

Abstract

IgA secreting plasma cells in the lamina propria are shown to be an important source of iNOS and TNF required to maintain the homeostatic balance between intestinal microbes and the immune system. The gut contains a vast number of bacteria that are essential for the health of the organism, but it is also a rich source of lymphocytes that exist to eliminate infections. How do lymphocytes restrain themselves from attacking beneficial bacteria, yet maintain their ability to respond to true pathogens? Fritz et al. show that as B cells differentiate into plasma cells in the gut, they adopt a phenotype reminiscent of innate immune cells — inflammatory monocytes — while maintaining their ability to produce immunoglobulin. The resulting immunoglobulin-A-secreting plasma cells in the lamina propria are shown to be the main source of the antimicrobial mediators tumour necrosis factor-α and inducible nitric oxide synthase, which are required to maintain the homeostatic balance between intestinal microbes and the immune system. The largest mucosal surface in the body is in the gastrointestinal tract, a location that is heavily colonized by microbes that are normally harmless. A key mechanism required for maintaining a homeostatic balance between this microbial burden and the lymphocytes that densely populate the gastrointestinal tract is the production and transepithelial transport of poly-reactive IgA (ref. 1). Within the mucosal tissues, B cells respond to cytokines, sometimes in the absence of T-cell help, undergo class switch recombination of their immunoglobulin receptor to IgA, and differentiate to become plasma cells2. However, IgA-secreting plasma cells probably have additional attributes that are needed for coping with the tremendous bacterial load in the gastrointestinal tract. Here we report that mouse IgA+ plasma cells also produce the antimicrobial mediators tumour-necrosis factor-α (TNF-α) and inducible nitric oxide synthase (iNOS), and express many molecules that are commonly associated with monocyte/granulocytic cell types. The development of iNOS-producing IgA+ plasma cells can be recapitulated in vitro in the presence of gut stroma, and the acquisition of this multifunctional phenotype in vivo and in vitro relies on microbial co-stimulation. Deletion of TNF-α 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.