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

Abstract

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.

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Figure 1: IgA + plasma cells in the small intestinal lamina propria can produce iNOS and TNF-α.
Figure 2: TNF-α and iNOS expression in IgA + plasma cells requires microbial exposure.
Figure 3: Reduced IgA production and altered commensal flora composition in iNOS/TNF-α double-deficient mixed chimaeric mice.
Figure 4: iNOS/TNF-α double-deficient mixed chimaeras are more susceptible to infection with C. rodentium.

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Acknowledgements

We thank D. White in the Faculty of Medicine Flow Cytometry core facility and H. Singh for critical reading of the manuscript. We thank E. Verdu for providing additional germ-free mice at short notice, and we also thank C. Guidos for numerous Rag2−/− mice for mixed bone marrow chimeras. C.J.P. is supported by a CIHR operating grant MOP number 9862. R.C. is supported in part by the Intramural Research Program of the National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institutes of Health. I.I.I. is supported by NIH (R00 DK085329-02) and CCFA (CDA #2388). A.M. is supported by a CIHR operating grant MOP number 89783. J.H.F. acknowledges support by an APART-fellowship of the Austrian Academy of Sciences, McGill start-up funds and a CIHR operating grant MOP number 114972. N.S. acknowledges the support of a CIHR Doctoral Award. J.L.G. is funded by the Canadian Institutes of Health Research (CIHR) and acknowledges the support of CIHR operating grant MOP number 67157 as well as infrastructure support from the Ontario Research Fund and that Canadian Foundation for Innovation. All authors have reviewed and agree with the content of the manuscript.

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J.H.F. generated data in Figs 1d–f, 3a–d, 4d–f and Supplementary Figs 2–4, 7 and 8. O.L.R. contributed data in Figs 1a–d, 3a, b, 4, Supplementary Figs 7, 8 and Supplementary Tables 1–3. N.S. and C.J.P. contributed data in Fig. 2b and Supplementary Fig. 6. D.D.M. contributed data in Figs 1a, b, 2a and Supplementary Figs 1–3. S.H. contributed data in Fig. 2a. A.M. and M.L. contributed Supplementary Fig. 1b (D.M. did the sort). R.C. provided AID–YFP mice. I.I.I. originally suggested that we examine IgA+ plasma cells as putative TNF-α/iNOS-producing cells and urged us to do the initial experiments. D.J.P and S.J.R. contributed data in Fig. 3e and provided critical insights. S.E.G. and S.R. helped us set up the Citrobacter rodentium experiments and provided critical insights. A.J.M., S.H. and K.D.M. provided intestinal tissues from germ-free and re-colonized mice. J.G. provided gene-deficient mice. J.L.G. wrote the manuscript and obtained funding for the work from the Canadian Institutes of Health Research.

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Correspondence to Jennifer L. Gommerman.

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The authors declare no competing financial interests.

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Fritz, J., Rojas, O., Simard, N. et al. Acquisition of a multifunctional IgA+ plasma cell phenotype in the gut. Nature 481, 199–203 (2012). https://doi.org/10.1038/nature10698

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