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.

  • Article
  • Published:

B cells regulate autoimmunity by provision of IL-10

Nature Immunology volume 3, pages 944–950 (2002)Cite this article

Abstract

To assess the importance of B cell control of T cell differentiation, we analyzed the course of the T helper type 1 (TH1)-driven disease experimental autoimmune encephalomyelitis in mice with an altered B cell compartment. We found that recovery was dependent on the presence of autoantigen-reactive B cells. B cells from recovered mice produced interleukin 10 (IL-10) in response to autoantigen. With a bone marrow chimeric system, we generated mice in which IL-10 deficiency was restricted to B cells but not T cells. In the absence of IL-10 production by B cells, the pro-inflammatory type 1 immune response persisted and mice did not recover. These data show that B cell–derived IL-10 plays a key role in controlling autoimmunity.

Access through your institution
Buy or subscribe

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

Access options

Access through your institution

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

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

Figure 1: Severe EAE in B cell–deficient mice correlates with uncontrolled type 1 autoreactivity.
Figure 2: B cells from recovered B6 mice produce MOG-specific IL-10.
Figure 3: B cell production of IL-10 is required for recovery from EAE.
Figure 4: Further analysis of the requirement for B cells in EAE recovery.
Figure 5: B cell IL-10 deficiency correlates with enhanced type 1 autoreactivity.
Figure 6: IL-10–producing B cells can transfer recovery from EAE.

Similar content being viewed by others

References

  1. Miller, J.F. & Basten, A. Mechanisms of tolerance to self. Curr. Opin. Immunol. 8, 815–821 (1996).

    Article  CAS  Google Scholar 

  2. Fulcher, D.A. et al. The fate of self-reactive B cells depends primarily on the degree of antigen receptor engagement and availability of T cell help. J. Exp. Med. 183, 2313–2328 (1996).

    Article  CAS  Google Scholar 

  3. Chan, O. & Shlomchik, M.J. A new role for B cells in systemic autoimmunity: B cells promote spontaneous T cell activation in MRL-lpr/lpr mice. J. Immunol. 160, 51–59 (1998).

    CAS  PubMed  Google Scholar 

  4. Martin, R. & McFarland, H.F. Immunological aspects of experimental allergic encephalomyelitis and multiple sclerosis. Crit. Rev. Clin. Lab. Sci. 32, 121–182 (1995).

    Article  CAS  Google Scholar 

  5. Kuchroo, V.K. et al. Cytokines and adhesion molecules contribute to the ability of myelin proteolipid protein-specific T cell clones to mediate experimental allergic encephalomyelitis. J. Immunol. 151, 4371–4382 (1993).

    CAS  PubMed  Google Scholar 

  6. Iglesias, A., Bauer, J., Litzenburger, T., Schubart, A. & Linington, C. T- and B-cell responses to myelin oligodendrocyte glycoprotein in experimental autoimmune encephalomyelitis and multiple sclerosis. Glia 36, 220–234 (2001).

    Article  CAS  Google Scholar 

  7. Myers, K.J., Sprent, J., Dougherty, J.P. & Ron, Y. Synergy between encephalitogenic T cells and myelin basic protein-specific antibodies in the induction of experimental autoimmune encephalomyelitis. J. Neuroimmunol. 41, 1–8 (1992).

    Article  CAS  Google Scholar 

  8. Wolf, S.D., Dittel, B.N., Hardardottir, F. & Janeway, C.A. Jr. Experimental autoimmune encephalomyelitis induction in genetically B cell-deficient mice. J. Exp. Med. 184, 2271–2278 (1996).

    Article  CAS  Google Scholar 

  9. Day, M.J., Tse, A.G., Puklavec, M., Simmonds, S.J. & Mason, D.W. Targeting autoantigen to B cells prevents the induction of a cell-mediated autoimmune disease in rats. J. Exp. Med. 175, 655–659 (1992).

    Article  CAS  Google Scholar 

  10. Saoudi, A., Simmonds, S., Huitinga, I. & Mason, D. Prevention of experimental allergic encephalomyelitis in rats by targeting autoantigen to B cells: evidence that the protective mechanism depends on changes in the cytokine response and migratory properties of the autoantigen-specific T cells. J. Exp. Med. 182, 335–344 (1995).

    Article  CAS  Google Scholar 

  11. Khoury, S.J., Hancock, W.W. & Weiner, H.L. Oral tolerance to myelin basic protein and natural recovery from experimental autoimmune encephalomyelitis are associated with downregulation of inflammatory cytokines and differential upregulation of transforming growth factor β, interleukin 4, and prostaglandin E expression in the brain. J. Exp. Med. 176, 1355–1364 (1992).

    Article  CAS  Google Scholar 

  12. Kennedy, M.K., Torrance, D.S., Picha, K.S. & Mohler, K.M. Analysis of cytokine mRNA expression in the central nervous system of mice with experimental autoimmune encephalomyelitis reveals that IL-10 mRNA expression correlates with recovery. J. Immunol. 149, 2496–2505 (1992).

    CAS  PubMed  Google Scholar 

  13. Bettelli, E. et al. IL-10 is critical in the regulation of autoimmune encephalomyelitis as demonstrated by studies of IL-10- and IL-4-deficient and transgenic mice. J. Immunol. 161, 3299–3306 (1998).

    CAS  Google Scholar 

  14. Samoilova, E.B., Horton, J.L. & Chen, Y. Acceleration of experimental autoimmune encephalomyelitis in interleukin-10-deficient mice: roles of interleukin-10 in disease progression and recovery. Cell. Immunol. 188, 118–124 (1998).

    Article  CAS  Google Scholar 

  15. Skok, J., Poudrier, J. & Gray, D. Dendritic cell-derived IL-12 promotes B cell induction of Th2 differentiation: a feedback regulation of Th1 development. J. Immunol. 163, 4284–4291 (1999).

    CAS  PubMed  Google Scholar 

  16. Kitamura, D. & Rajewsky, K. Targeted disruption of μ chain membrane exon causes loss of heavy-chain allelic exclusion. Nature 356, 154–156 (1992).

    Article  CAS  Google Scholar 

  17. Mendel, I., Derosbo, N.K. & Bennun, A. A myelin oligodendrocyte glycoprotein peptide induces typical chronic experimental autoimmune encephalomyelitis in H-2(B) mice - fine specificity and T-cell receptor V-β expression of encephalitogenic T-cells. Eur. J. Immunol. 25, 1951–1959 (1995).

    Article  CAS  Google Scholar 

  18. Lyons, J.A., San, M., Happ, M.P. & Cross, A.H. B cells are critical to induction of experimental allergic encephalomyelitis by protein but not by a short encephalitogenic peptide. Eur. J. Immunol. 29, 3432–3439 (1999).

    Article  CAS  Google Scholar 

  19. Goodnow, C.C. et al. Altered immunoglobulin expression and functional silencing of self-reactive B lymphocytes in transgenic mice. Nature 334, 676–682 (1988).

    Article  CAS  Google Scholar 

  20. Mauri, C., Mars, L.T. & Londei, M. Therapeutic activity of agonistic monoclonal antibodies against CD40 in a chronic autoimmune inflammatory process. Nature Med. 6, 673–679 (2000).

    Article  CAS  Google Scholar 

  21. Mizoguchi, A., Mizoguchi, E., Takedatsu, H., Blumberg, R.S. & Bhan, A.K. Chronic intestinal inflammatory condition generates IL-10-producing regulatory B cell subset characterized by CD1d upregulation. Immunity 16, 219–230 (2002).

    Article  CAS  Google Scholar 

  22. Singh, A.K. et al. Natural killer T cell activation protects mice against experimental autoimmune encephalomyelitis. J. Exp. Med. 194, 1801–1811 (2001).

    Article  CAS  Google Scholar 

  23. Colgan, S.P., Hershberg, R.M., Furuta, G.T. & Blumberg, R.S. Ligation of intestinal epithelial CD1d induces bioactive IL-10: critical role of the cytoplasmic tail in autocrine signaling. Proc. Natl. Acad. Sci. USA 96, 13938–13943 (1999).

    Article  CAS  Google Scholar 

  24. Herzenberg, L.A. B-1 cells: the lineage question revisited. Immunol. Rev. 175, 9–22 (2000).

    Article  CAS  Google Scholar 

  25. Rothstein, T.L. Cutting edge commentary: two B-1 or not to be one. J. Immunol. 168, 4257–4261 (2002).

    Article  CAS  Google Scholar 

  26. O'Garra, A. et al. Ly-1 B (B-1) cells are the main source of B cell-derived interleukin 10. Eur. J. Immunol. 22, 711–717 (1992).

    Article  CAS  Google Scholar 

  27. Whitmore, A.C., Haughton, G. & Arnold, L.W. Phenotype of B cells responding to the thymus-independent type-2 antigen polyvinyl pyrrolidinone. Int. Immunol. 8, 533–542 (1996).

    Article  CAS  Google Scholar 

  28. Segal, B.M., Dwyer, B.K. & Shevach, E.M. An interleukin (IL)-10/IL-12 immunoregulatory circuit controls susceptibility to autoimmune disease. J. Exp. Med. 187, 537–546 (1998).

    Article  CAS  Google Scholar 

  29. Xiao, B.G., Bai, X.F., Zhang, G.X. & Link, H. Suppression of acute and protracted-relapsing experimental allergic encephalomyelitis by nasal administration of low-dose IL-10 in rats. J. Neuroimmunol. 84, 230–237 (1998).

    Article  CAS  Google Scholar 

  30. Cannella, B., Gao, Y.L., Brosnan, C. & Raine, C.S. IL-10 fails to abrogate experimental autoimmune encephalomyelitis. J. Neurosci. Res. 45, 735–746 (1996).

    Article  CAS  Google Scholar 

  31. Croxford, J.L., Feldmann, M., Chernajovsky, Y. & Baker, D. Different therapeutic outcomes in experimental allergic encephalomyelitis dependent upon the mode of delivery of IL-10: a comparison of the effects of protein, adenoviral or retroviral IL-10 delivery into the central nervous system. J. Immunol. 166, 4124–4130 (2001).

    Article  CAS  Google Scholar 

  32. Mathisen, P.M., Yu, M., Johnson, J.M., Drazba, J.A. & Tuohy, V.K. Treatment of experimental autoimmune encephalomyelitis with genetically modified memory T cells. J. Exp. Med. 186, 159–164 (1997).

    Article  CAS  Google Scholar 

  33. Cua, D.J., Groux, H., Hinton, D.R., Stohlman, S.A. & Coffman, R.L. Transgenic interleukin 10 prevents induction of experimental autoimmune encephalomyelitis. J. Exp. Med. 189, 1005–1010 (1999).

    Article  CAS  Google Scholar 

  34. Stockinger, B., Zal, T., Zal, A. & Gray, D. B cells solicit their own help from T cells. J. Exp. Med. 183, 891–899 (1996).

    Article  CAS  Google Scholar 

  35. Macaulay, A.E., DeKruyff, R.H., Goodnow, C.C. & Umetsu, D.T. Antigen-specific B cells preferentially induce CD4+ T cells to produce IL-4. J. Immunol. 158, 4171–4179 (1997).

    CAS  PubMed  Google Scholar 

  36. Harris, D.P. et al. Reciprocal regulation of polarized cytokine production by effector B and T cells. Nature Immunol. 1, 475–482 (2000).

    Article  CAS  Google Scholar 

  37. Moulin, V. et al. B lymphocytes regulate dendritic cell (DC) function in vivo: increased interleukin 12 production by DCs from B cell-deficient mice results in T helper cell type 1 deviation. J. Exp. Med. 192, 475–482 (2000).

    Article  CAS  Google Scholar 

  38. Maldonado-Lopez, R., Maliszewski, C., Urbain, J. & Moser, M. Cytokines regulate the capacity of CD8α(+) and CD8α(−) dendritic cells to prime Th1/Th2 cells in vivo. J. Immunol. 167, 4345–4350 (2001).

    Article  CAS  Google Scholar 

  39. D'Amico, G. et al. Uncoupling of inflammatory chemokine receptors by IL-10: generation of functional decoys. Nature Immunol. 1, 387–391 (2000).

    Article  CAS  Google Scholar 

  40. Cumberbatch, M., Dearman, R.J. & Kimber, I. Langerhans cells require signals from both tumour necrosis factor-α and interleukin-1β for migration. Immunology 92, 388–395 (1997).

    Article  CAS  Google Scholar 

  41. Kuhn, R., Lohler, J., Rennick, D., Rajewsky, K. & Muller, W. Interleukin-10-deficient mice develop chronic enterocolitis. Cell 75, 263–274 (1993).

    Article  CAS  Google Scholar 

  42. Kawabe, T. et al. The immune responses in CD40-deficient mice: impaired immunoglobulin class switching and germinal center formation. Immunity 1, 167–178 (1994).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  44. Beech, J.T., Bainbridge, T. & Thompson, S.J. Incorporation of cells into an ELISA system enhances antigen-driven lymphokine detection. J. Immunol. Meth. 205, 163–168 (1997).

    Article  CAS  Google Scholar 

  45. Rolink, A., Melchers, F. & Andersson, J. The SCID but not the RAG-2 gene product is required for Sμ-Sɛ heavy chain class switching. Immunity 5, 319–330 (1996).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

Supported by grants from the Medical Research Council UK and the Wellcome Trust and by the Wellcome Trust (D.G.) and Medical Research Council (S. M. A).

Author information

Authors and Affiliations

  1. University of Edinburgh, Institute of Cell, Animal and Population Biology, King's Buildings West Mains Road, Edinburgh, EH9 3JT, UK

    Simon Fillatreau, Claire H. Sweenie, Mandy J. McGeachy, David Gray & Stephen M. Anderton

Authors
  1. Simon Fillatreau
    View author publications

    You can also search for this author inPubMed Google Scholar

  2. Claire H. Sweenie
    View author publications

    You can also search for this author inPubMed Google Scholar

  3. Mandy J. McGeachy
    View author publications

    You can also search for this author inPubMed Google Scholar

  4. David Gray
    View author publications

    You can also search for this author inPubMed Google Scholar

  5. Stephen M. Anderton
    View author publications

    You can also search for this author inPubMed Google Scholar

Corresponding author

Correspondence to Stephen M. Anderton.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Fillatreau, S., Sweenie, C., McGeachy, M. et al. B cells regulate autoimmunity by provision of IL-10. Nat Immunol 3, 944–950 (2002). https://doi.org/10.1038/ni833

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ni833

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