Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Regulation of IgA production by naturally occurring TNF/iNOS-producing dendritic cells

Abstract

Immunoglobulin-A has an irreplaceable role in the mucosal defence against infectious microbes1,2,3,4,5,6. In human and mouse, IgA-producing plasma cells comprise 20% of total plasma cells of peripheral lymphoid tissues, whereas more than 80% of plasma cells produce IgA in mucosa-associated lymphoid tissues (MALT)1,2,3,4,5,6. One of the most biologically important and long-standing questions in immunology is why this ‘biased’ IgA synthesis takes place in the MALT but not other lymphoid organs. Here we show that IgA class-switch recombination (CSR) is impaired in inducible-nitric-oxide-synthase-deficient (iNOS-/-; gene also called Nos2) mice. iNOS regulates the T-cell-dependent IgA CSR through expression of transforming growth factor-β receptor, and the T-cell-independent IgA CSR through production of a proliferation-inducing ligand (APRIL, also called Tnfsf13) and a B-cell-activating factor of the tumour necrosis factor (TNF) family (BAFF, also called Tnfsf13b). Notably, iNOS is preferentially expressed in MALT dendritic cells in response to the recognition of commensal bacteria by toll-like receptor. Furthermore, adoptive transfer of iNOS+ dendritic cells rescues IgA production in iNOS-/- mice. Further analysis revealed that the MALT dendritic cells are a TNF-α/iNOS-producing dendritic-cell subset, originally identified in mice infected with Listeria monocytogenes7,8. The presence of a naturally occurring TNF-α/iNOS-producing dendritic-cell subset may explain the predominance of IgA production in the MALT, critical for gut homeostasis.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1: IgA reduction in iNOS -/- mice.
Figure 2: Impaired T-cell-dependent IgA CSR in iNOS -/- mice.
Figure 3: Impaired T-cell-independent CSR in iNOS -/- mice.
Figure 4: Identification of iNOS + dendritic cells in the MALT.

References

  1. Brandtzaeg, P. et al. Regional specialization in the mucosal immune system: what happens in the microcompartments? Immunol. Today 20, 141–151 (1999)

    Article  CAS  Google Scholar 

  2. van Egmond, M. et al. IgA and the IgA Fc receptor. Trends Immunol. 22, 205–211 (2001)

    Article  CAS  Google Scholar 

  3. Mostov, K. E. Transepithelial transport of immunoglobulins. Annu. Rev. Immunol. 12, 63–84 (1994)

    Article  CAS  Google Scholar 

  4. Matsunaga, T. & Rahman, A. What brought the adaptive immune system to vertebrates?—The jaw hypothesis and the seahorse. Immunol. Rev. 166, 177–186 (1998)

    Article  CAS  Google Scholar 

  5. Fagarasan, S. & Honjo, T. Intestinal IgA synthesis: regulation of front-line body defences. Nature Rev. Immunol. 3, 63–72 (2003)

    Article  CAS  Google Scholar 

  6. Suzuki, K. et al. Aberrant expansion of segmented filamentous bacteria in IgA-deficient gut. Proc. Natl Acad. Sci. USA 101, 1981–1986 (2004)

    Article  ADS  CAS  Google Scholar 

  7. Serbina, N. V., Salazar-Mather, T. P., Biron, C. A., Kuziel, W. A. & Pamer, E. G. TNF/iNOS-producing dendritic cells mediate innate immune defense against bacterial infection. Immunity 19, 59–70 (2003)

    Article  CAS  Google Scholar 

  8. Serbina, N. V. & Pamer, E. G. Monocyte emigration from bone marrow during bacterial infection requires signals mediated by chemokine receptor CCR2. Nature Immunol. 7, 311–317 (2006)

    Article  CAS  Google Scholar 

  9. Macpherson, A. J. & Uhr, T. Induction of protective IgA by intestinal dendritic cells carrying commensal bacteria. Science 303, 1662–1665 (2004)

    Article  ADS  CAS  Google Scholar 

  10. Macpherson, A. J. et al. A primitive T cell-independent mechanism of intestinal mucosal IgA responses to commensal bacteria. Science 288, 2222–2226 (2000)

    Article  ADS  CAS  Google Scholar 

  11. Litinskiy, M. B. et al. DCs induce CD40-independent immunoglobulin class switching through BLyS and APRIL. Nature Immunol. 3, 822–829 (2002)

    Article  CAS  Google Scholar 

  12. Castigli, E. et al. TACI and BAFF-R mediate isotype switching in B cells. J. Exp. Med. 201, 35–39 (2005)

    Article  CAS  Google Scholar 

  13. Mestecky, J. & McGhee, J. R. Immunoglobulin A (IgA): molecular and cellular interactions involved in IgA biosynthesis and immune response. Adv. Immunol. 40, 153–245 (1987)

    Article  CAS  Google Scholar 

  14. Fagarasan, S., Kinoshita, K., Muramatsu, M., Ikuta, K. & Honjo, T. In situ class switching and differentiation to IgA-producing cells in the gut lamina propria. Nature 413, 639–643 (2001)

    Article  ADS  CAS  Google Scholar 

  15. Bogdan, C. Nitric oxide and the immune response. Nature Immunol. 2, 907–916 (2001)

    Article  CAS  Google Scholar 

  16. Fujihashi, K. et al. γ/δ T cell-deficient mice have impaired mucosal immunoglobulin A responses. J. Exp. Med. 183, 1929–1935 (1996)

    Article  CAS  Google Scholar 

  17. Shimada, S.-I. et al. Generation of polymeric immunoglobulin receptor-deficient mouse with marked reduction of secretory IgA. J. Immunol. 163, 5367–5373 (1999)

    CAS  PubMed  Google Scholar 

  18. Muramatsu, M. et al. Class switch recombination and hypermutation require activation-induced cytidine deaminase (AID), a potential RNA editing enzyme. Cell 102, 553–563 (2000)

    Article  CAS  Google Scholar 

  19. Cazac, B. B. & Roes, J. TGF-β receptor controls B cell responsiveness and induction of IgA in vivo. Immunity 13, 443–451 (2000)

    Article  CAS  Google Scholar 

  20. Borsutzky, S., Cazac, B. B., Roes, J. & Guzman, C. A. TGF-β receptor signaling is critical for mucosal IgA responses. J. Immunol. 173, 3305–3309 (2004)

    Article  CAS  Google Scholar 

  21. Park, S. R., Lee, J. H. & Kim, P. H. Smad3 and Smad4 mediate transforming growth factor-β1-induced IgA expression in murine B lymphocytes. Eur. J. Immunol. 31, 1706–1715 (2001)

    Article  CAS  Google Scholar 

  22. Fainaru, O. et al. Runx3 regulates mouse TGF-β-mediated dendritic cell function and its absence results in airway inflammation. EMBO J. 23, 969–979 (2004)

    Article  CAS  Google Scholar 

  23. Castigli, E. et al. Impaired IgA class switching in APRIL-deficient mice. Proc. Natl Acad. Sci. USA 101, 3903–3908 (2004)

    Article  ADS  CAS  Google Scholar 

  24. von Bulow, G.-U., van Deursen, J. M. & Bram, R. J. Regulation of the T-independent humoral response by TACI. Immunity 14, 573–582 (2001)

    Article  CAS  Google Scholar 

  25. He, B., Raab-Traub, N., Casali, P. & Cerutti, A. EBV-encoded latent membrane protein 1 cooperates with BAFF/BLyS and APRIL to induce T cell-independent Ig heavy chain class switching. J. Immunol. 171, 5215–5224 (2003)

    Article  CAS  Google Scholar 

  26. Iwata, M. et al. Retinoic acid imprints gut-homing specificity on T cells. Immunity 21, 527–538 (2004)

    Article  CAS  Google Scholar 

  27. Mora, J. R. et al. Generation of gut-homing IgA-secreting B cells by intestinal dendritic cells. Science 314, 1157–1160 (2006)

    Article  ADS  CAS  Google Scholar 

  28. Rakoff-Nahoum, S., Paglino, J., Eslami-Varzaneh, F., Edberg, S. & Medzhitov, R. Recognition of commensal microflora by toll-like receptors is required for intestinal homeostasis. Cell 118, 229–241 (2004)

    Article  CAS  Google Scholar 

  29. Rescigno, M. et al. Dendritic cells express tight junction proteins and penetrate gut epithelial monolayers to sample bacteria. Nature Immunol. 2, 361–367 (2001)

    Article  CAS  Google Scholar 

  30. Niess, J. H. et al. CX3CR1-mediated dendritic cell access to the intestinal lumen and bacterial clearance. Science 307, 254–258 (2005)

    Article  ADS  CAS  Google Scholar 

  31. Nishiyama, Y. et al. Homeostatic regulation of intestinal villous epithelia by B lymphocytes. J. Immunol. 168, 2626–2633 (2002)

    Article  CAS  Google Scholar 

  32. Adachi, O. et al. Targeted disruption of the MyD88 gene results in loss of IL-1- and IL-18-mediated function. Immunity 9, 143–150 (1998)

    Article  CAS  Google Scholar 

  33. Kitamura, D., Roes, J., Kuhn, R. & Rajewsky, K. A B cell-deficient mouse by targeted disruption of the membrane exon of the immunoglobulin μ chain gene. Nature 350, 423–426 (1991)

    Article  ADS  CAS  Google Scholar 

  34. Noguchi, H., Matsushita, M., Okitsu, T. & Matsui, H. A new cell-permeable peptide allows successful allogeneic islet transplantation in mice. Nature Med. 10, 305–309 (2004)

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank K. Onodera for animal care; K. Yamashita for experimental support; K. Honda, M. Muramatsu and M. Miyasaka for discussions; M. Nanno for BALB/c germ-free mice; T. Tsubata for B6.μMt mice; and K. Takatsu for monoclonal antibody H-7. This work was supported by Yakult Bio-Science Foundation (to T.O.), a Sasakawa Scientific Research Grant from The Japan Science Society (to H. Tezuka), a Grant-in-Aid for Scientific Research on Priority Areas from the Ministry of Education, Science, Sports and Culture of Japan (T.O.), and a Grant-in-Aid for Young Scientists (B) (to H. Tezuka.).

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Toshiaki Ohteki.

Ethics declarations

Competing interests

Reprints and permissions information is available at www.nature.com/reprints. The authors declare no competing financial interests.

Supplementary information

Supplementary Figures

This file contains Supplementary Figures 1-6 with Legends. These provide data that corroborate the main findings of the text. (PDF 1097 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Tezuka, H., Abe, Y., Iwata, M. et al. Regulation of IgA production by naturally occurring TNF/iNOS-producing dendritic cells. Nature 448, 929–933 (2007). https://doi.org/10.1038/nature06033

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nature06033

This article is cited by

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing