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

Nature volume 448, pages 929–933 (2007)Cite this article

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.

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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.

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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.).

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Authors and Affiliations

  1. Department of Immunology, Akita University Graduate School of Medicine, Akita 010-8543, Japan

    Hiroyuki Tezuka, Yukiko Abe & Toshiaki Ohteki

  2. Faculty of Pharmaceutical Sciences at Kagawa Campus, Tokushima Bunri University, Kagawa 769-2193, Japan

    Makoto Iwata & Hajime Takeuchi

  3. Department of Microbiology and Immunology, Keio University School of Medicine, Tokyo 160-8582, Japan

    Hiromichi Ishikawa

  4. Mitsubishi Kagaku Institute of Life Sciences, Tokyo 194-8511, Japan

    Masayuki Matsushita

  5. Department of Dermatology, Kyorin University School of Medicine, Tokyo 181-8611, Japan

    Tetsuo Shiohara

  6. Department of Host Defense, Research Institute for Microbial Diseases, Osaka University, Osaka 565-0871, Japan

    Shizuo Akira

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  1. Hiroyuki Tezuka
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Correspondence to Toshiaki Ohteki.

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

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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

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