Acquisition of a multifunctional [IgA.sup.+] plasma cell phenotype in the gut

• Published in: Nature (London) 2012-01, Vol.481 (7380), p.199
• Main Authors: Fritz, Jorg H, Rojas, Olga Lucia, Simard, Nathalie, McCarthy, Douglas D, Hapfelmeier, Siegfried, Rubino, Stephen, Robertson, Susan J, Larijani, Mani, Gosselin, Jean, Ivanov, Ivaylo I, Martin, Alberto, Casellas, Rafael, Philpott, Dana J, Girardin, Stephen E, McCoy, Kathy D, Macpherson, Andrew J, Paige, Christopher J, Gommerman, Jennifer L
• Format: Article
• Language: English
• Subjects: Gene expression; Microbiota (Symbiotic organisms); Physiological aspects; Plasma cells; Tumor necrosis factor
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/naturel0698

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.sup.+], and differentiate to become plasma cells (2). However, [IgA.sup.+]-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.sup.+] 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.sup.+] 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.sup.+] 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.