Acquisition of a multifunctional IgA+ plasma cell phenotype in the gut (original) (raw)

Nature volume 481, pages 199–203 (2012) Cite this article

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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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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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Author notes

  1. Jörg H. Fritz, Siegfried Hapfelmeier & Mani Larijani
    Present address: Present addresses: Complex Traits Group, Department of Microbiology and Immunology, McGill University, Montreal H3G 0B1, Canada (J.H.F.); University of Bern, Institute of Infectious Disease, Friedbühlstrasse 51, 3010 Bern, Switzerland (S.H.); Division of Biomedical Sciences, Faculty of Medicine, Memorial University of Newfoundland, St John’s A1B 3V6, Canada (M.L.).,
  2. Jörg H. Fritz and Olga Lucia Rojas: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Immunology, University of Toronto, Toronto, M5S 1A8, Canada
    Jörg H. Fritz, Olga Lucia Rojas, Nathalie Simard, Douglas D. McCarthy, Susan J. Robertson, Mani Larijani, Alberto Martin, Dana J. Philpott, Christopher J. Paige & Jennifer L. Gommerman
  2. Ontario Cancer Institute, Princess Margaret Hospital, University Health Network, Toronto, M5G 2M9, Canada
    Nathalie Simard & Christopher J. Paige
  3. Department Klinische Forschung (Gastroenterologie), University of Bern, Mutenstrasse 35, Bern, 3010, Switzerland
    Siegfried Hapfelmeier, Kathy D. McCoy & Andrew J. Macpherson
  4. Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, M5S 1A8, Canada
    Stephen Rubino & Stephen E. Girardin
  5. Department of Molecular Medicine, University of Laval, G1V 4G2, Quebec, Canada
    Jean Gosselin
  6. Department of Microbiology and Immunology, Columbia University Medical Center, College of Physicians and Surgeons, New York, 10032, New York, USA
    Ivaylo I. Ivanov
  7. Genomics and Immunity, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, 20892, Maryland, USA
    Rafael Casellas

Authors

  1. Jörg H. Fritz
  2. Olga Lucia Rojas
  3. Nathalie Simard
  4. Douglas D. McCarthy
  5. Siegfried Hapfelmeier
  6. Stephen Rubino
  7. Susan J. Robertson
  8. Mani Larijani
  9. Jean Gosselin
  10. Ivaylo I. Ivanov
  11. Alberto Martin
  12. Rafael Casellas
  13. Dana J. Philpott
  14. Stephen E. Girardin
  15. Kathy D. McCoy
  16. Andrew J. Macpherson
  17. Christopher J. Paige
  18. Jennifer L. Gommerman

Contributions

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.

Corresponding author

Correspondence toJennifer 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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Editorial Summary

Gut lymphocytes strike a balance

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.