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.

  • Letter
  • Published:

In situ class switching and differentiation to IgA-producing cells in the gut lamina propria

Nature volume 413, pages 639–643 (2001)Cite this article

Abstract

One of the front lines of the immune defence is the gut mucosa, where immunoglobulin-α (IgA) is continuously produced to react with commensal bacteria and dietary antigens. It is generally accepted that, after antigenic stimulation in the Peyer's patches, IgA+ lymphoblasts (B220+IgA+) migrate through the lymph and blood circulation, and eventually home to the lamina propria of the intestine1,2. Mice that lack activation-induced cytidine deaminase (AID) are defective in class switch recombination (CSR) and somatic hypermutation3. CSR changes the immunoglobulin heavy chain constant region (CH) gene being expressed from Cµ to other CH genes, resulting in a switch of the immunoglobulin isotype from IgM to IgG, IgE or IgA. AID-/- mice also secrete large amounts of immunoglobulin-µ (IgM) into faeces, and accumulate B220-IgM+ plasma cells as well as B220+IgM+ cells in the gut. Here we show that lamina propria B220+IgA+ cells have just completed CSR, as they still express both AID and transcripts from circular DNA that has been ‘looped-out’ during CSR. Lamina propria IgM+ B cells seem to be pre-committed to switching to IgA+ in vitro as well as in vivo. Culturing lamina propria IgM+ B cells together with lamina propria stromal cells enhances preferential switching and differentiation of B cells to IgA+ plasma cells. We conclude that IgA+ cells in the gut lamina propria are generated in situ from B220+IgM+ lymphocytes.

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

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

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

Figure 1: Accumulation of B220-IgM+ plasma cells and B220+IgM+ B cells in the LP of aged AID-/- mice.
Figure 2: Active CSR in B220+IgA+ cells of the LP.
Figure 3: In vivo LP IgM+ B cells generate IgA-producing cells rapidly and efficiently.
Figure 4: LP-SCs support preferential switching and differentiation to IgA+ plasma cells.

Similar content being viewed by others

References

  1. Craig, S. W. & Cebra, J. J. Peyer's patches: an enriched source of precursors for IgA-producing immunocytes in the rabbit. J. Exp. Med. 134, 188–200 (1971).

    Article  CAS  Google Scholar 

  2. Tseng, J. Transfer of lymphocytes of Peyer's patches between immunoglobulin allotype congenic mice: repopulation of the IgA plasma cells in the gut lamina propria. J. Immunol. 127, 2039–2043 (1981).

    CAS  PubMed  Google Scholar 

  3. 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 

  4. Kamata, T. et al. Increased frequency of surface IgA-positive plasma cells in the intestinal lamina propria and decreased IgA excretion in hyper IgA (HIGA) mice, a murine model of IgA nephropathy with hyperserum IgA. J. Immunol. 165, 1387–1394 (2000).

    Article  CAS  Google Scholar 

  5. Lebman, D. A., Griffin, P. M. & Cebra, J. J. Relationship between expression of IgA by Peyer's patch cells and functional IgA memory cells. J. Exp. Med. 166, 1405–1418 (1987).

    Article  CAS  Google Scholar 

  6. Muramatsu, M. et al. Specific expression of activation-induced cytidine deaminase (AID), a novel member of the RNA-editing deaminase family in germinal center B cells. J. Biol. Chem. 274, 18470–18476 (1999).

    Article  CAS  Google Scholar 

  7. Stavnezer-Nordgren, J. & Sirlin, S. Specificity of immunoglobulin heavy chain switch correlates with activity of germline heavy chain genes prior to switching. EMBO J. 5, 95–102 (1986).

    Article  CAS  Google Scholar 

  8. Iwasato, T., Shimizu, A., Honjo, T. & Yamagishi, H. Circular DNA is excised by immunoglobulin class switch recombination. Cell 62, 143–149 (1990).

    Article  CAS  Google Scholar 

  9. Nakamura, M. et al. High frequency class switching of an IgM+B lymphoma clone CH12F3 to IgA+ cells. Int. Immunol. 8, 193–201 (1996).

    Article  CAS  Google Scholar 

  10. Waldschmidt, T. J., Conrad, D. H. & Lynch, R. G. The expression of B cell surface receptors. I. The ontogeny and distribution of the murine B cell IgE Fc receptor. J. Immunol. 140, 2148–2154 (1988).

    CAS  PubMed  Google Scholar 

  11. Waldschmidt, T. J., Kroese, F. G., Tygrett, L. T., Conrad, D. H. & Lynch, R. G. The expression of B cell surface receptors. III. The murine low-affinity IgE Fc receptor is not expressed on Ly 1 or ‘Ly 1-like’ B cells. Int. Immunol. 3, 305–315 (1991).

    Article  CAS  Google Scholar 

  12. Oliver, A. M., Martin, F., Gartland, G. L., Carter, R. H. & Kearney, J. F. Marginal zone B cells exhibit unique activation, proliferative and immunoglobulin secretory responses. Eur. J. Immunol. 27, 2366–2374 (1997).

    Article  CAS  Google Scholar 

  13. Martin, F. & Kearney, J. F. CD21highIgMhigh splenic B cells enriched in the marginal zone: distinct phenotypes and functions. Curr. Top. Microbiol. Immunol. 246, 45–50 (1999).

    CAS  PubMed  Google Scholar 

  14. Whitlock, C. A., Tidmarsh, G. F., Muller-Sieburg, C. & Weissman, I. L. Bone marrow stromal cell lines with lymphopoietic activity express high levels of a pre-B neoplasia-associated molecule. Cell 48, 1009–1021 (1987).

    Article  CAS  Google Scholar 

  15. Xu, J. et al. Mice deficient for the CD40 ligand. Immunity 1, 423–431 (1994).

    Article  CAS  Google Scholar 

  16. Renshaw, B. R. et al. Humoral immune responses in CD40 ligand-deficient mice. J. Exp. Med. 180, 1889–1900 (1994).

    Article  CAS  Google Scholar 

  17. Coffman, R. L., Lebman, D. A. & Shrader, B. Transforming growth factor β specifically enhances IgA production by lipopolysaccharide-stimulated murine B lymphocytes. J. Exp. Med. 170, 1039–1044 (1989).

    Article  CAS  Google Scholar 

  18. Sonoda, E. et al. Transforming growth factor β induces IgA production and acts additively with interleukin 5 for IgA production. J. Exp. Med. 170, 1415–1420 (1989).

    Article  CAS  Google Scholar 

  19. Ramsay, A. J. et al. The role of interleukin-6 in mucosal IgA antibody responses in vivo. Science 264, 561–563 (1994).

    Article  ADS  CAS  Google Scholar 

  20. Shparago, N. et al. IL-10 selectively regulates murine Ig isotype switching. Int. Immunol. 8, 781–790 (1996).

    Article  CAS  Google Scholar 

  21. 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 

  22. Kroese, F. G. et al. Many of the IgA producing plasma cells in murine gut are derived from self-replenishing precursors in the peritoneal cavity. Int. Immunol. 1, 75–84 (1989).

    Article  CAS  Google Scholar 

  23. 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 

  24. Fagarasan, S., Watanabe, N. & Honjo, T. Generation, expansion, migration and activation of mouse B1 cells. Immunol. Rev. 176, 205–215 (2000).

    Article  CAS  Google Scholar 

  25. Fagarasan, S. & Honjo, T. T-independent immune response: new aspects of B cell biology. Science 290, 89–92 (2000).

    Article  ADS  CAS  Google Scholar 

  26. Watanabe, N. et al. Migration and differentiation of autoreactive B-1 cells induced by activated γ/δ T cells in antierythrocyte immunoglobulin transgenic mice. J. Exp. Med. 192, 1577–1586 (2000).

    Article  CAS  Google Scholar 

  27. Fagarasan, S. et al. Alymphoplasia (aly)-type nuclear factor κB-inducing kinase (NIK) causes defects in secondary lymphoid tissue chemokine receptor signaling and homing of peritoneal cells to the gut-associated lymphatic tissue system. J. Exp. Med. 191, 1477–1486 (2000).

    Article  CAS  Google Scholar 

  28. Ikuta, K. et al. A developmental switch in thymic lymphocyte maturation potential occurs at the level of hematopoietic stem cells. Cell 62, 863–874 (1990).

    Article  CAS  Google Scholar 

  29. Ye, S. K. et al. Induction of germline transcription in the TCRγ locus by Stat5: implications for accessibility control by the IL-7 receptor. Immunity 11, 213–223 (1999).

    Article  CAS  Google Scholar 

  30. Morita, S., Kojima, T. & Kitamura, T. Plat-E: an efficient and stable system for transient packaging of retroviruses. Gene Ther. 7, 1063–1066 (2000).

    Article  CAS  Google Scholar 

  31. Kinoshita, K., Harigai, M., Fagarasan, S., Muramatsu, M. & Honjo, T. A hallmark of active class switch recombination: Transcripts directed by I promoters on looped-out circular DNAs. Proc. Natl. Acad. Sci. USA (in the press).

Download references

Acknowledgements

We are especially grateful to M. Tanaka for cell sorting, and to Y. Tabuchi, T. Toyoshima and E. Inoue for their technical assistance. This work was supported by Center of Excellence Grant from the Ministry of Education, Science, Sports and Culture of Japan.

Author information

Authors and Affiliations

  1. Department of Medical Chemistry, Graduate School of Medicine, Kyoto University, Yoshida Konoe-cho, Sakyo-ku, 606-8501, Kyoto, Japan

    Sidonia Fagarasan, Kazuo Kinoshita, Masamichi Muramatsu, Koichi Ikuta & Tasuku Honjo

Authors
  1. Sidonia Fagarasan
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Kazuo Kinoshita
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Masamichi Muramatsu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Koichi Ikuta
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Tasuku Honjo
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Tasuku Honjo.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Fagarasan, S., Kinoshita, K., Muramatsu, M. et al. In situ class switching and differentiation to IgA-producing cells in the gut lamina propria. Nature 413, 639–643 (2001). https://doi.org/10.1038/35098100

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/35098100

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

Advanced 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