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:

Maintenance of B cell anergy requires constant antigen receptor occupancy and signaling

Nature Immunology volume 6, pages 1160–1167 (2005)Cite this article

Abstract

Immunological tolerance can be mediated by anergy, in which self-reactive B cells persist in the periphery yet remain unresponsive to immunogen. Whether anergy is induced after transient exposure to self antigen and is 'remembered' or requires continuous antigen receptor occupancy and transduction of signals remains unclear. We have explored this using an immunoglobulin-transgenic mouse in which B cells were hapten specific (arsonate) yet cross-reacted with a self antigen that induced anergy in vivo. Many features of anergic cells were rapidly reversed after dissociation of self antigen using hapten competition and these cells regained antigen responsiveness. Our findings indicate that continuous binding of antigen and subsequent receptor signaling are essential for the maintenance of anergy.

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: Ars/A1 B cells show increased basal [Ca2+]i that is modulated by hapten competition.
Figure 2: Treatment of NP-specific B cells with monovalent hapten terminates BCR-mediated calcium signaling.
Figure 3: Treatment of antigen-bound B1-8 B cells with monovalent NIP dissociates antigen from the cell surface.
Figure 4: High basal [Ca2+]i in Ars/A1 mice is dependent on low-intensity signaling.
Figure 5: Hapten competition reduces Erk MAP kinase phosphorylation and expression of activation markers.
Figure 6: Hapten competition modulates the in vitro lifespan of anergic Ars/A1 B cells.
Figure 7: Recovery of BCR-mediated calcium mobilization by self antigen competition.
Figure 8: Hapten competition restores BCR-mediated CD86 upregulation.

Similar content being viewed by others

References

  1. Wardemann, H. et al. Predominant autoantibody production by early human B cell precursors. Science 301, 1374–1377 (2003).

    Article  CAS  Google Scholar 

  2. Grandien, A., Fucs, R., Nobrega, A., Andersson, J. & Coutinho, A. Negative selection of multireactive B cell clones in normal adult mice. Eur. J. Immunol. 24, 1345–1352 (1994).

    Article  CAS  Google Scholar 

  3. Benschop, R.J. et al. Activation and anergy in bone marrow B cells of a novel immunoglobulin transgenic mouse that is both hapten specific and autoreactive. Immunity 14, 33–43 (2001).

    Article  CAS  Google Scholar 

  4. Glynne, R., Ghandour, G., Rayner, J., Mack, D.H. & Goodnow, C.C. B-lymphocyte quiescence, tolerance and activation as viewed by global gene expression profiling on microarrays. Immunol. Rev. 176, 216–246 (2000).

    Article  CAS  Google Scholar 

  5. Healy, J.I. & Goodnow, C.C. Positive versus negative signaling by lymphocyte antigen receptors. Annu. Rev. Immunol. 16, 645–670 (1998).

    Article  CAS  Google Scholar 

  6. Mason, D.Y., Jones, M. & Goodnow, C.C. Development and follicular localization of tolerant B lymphocytes in lysozyme/anti-lysozyme IgM/IgD transgenic mice. Int. Immunol. 4, 163–175 (1992).

    Article  CAS  Google Scholar 

  7. 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 

  8. Goodnow, C.C., Crosbie, J., Jorgensen, H., Brink, R.A. & Basten, A. Induction of self-tolerance in mature peripheral B lymphocytes. Nature 342, 385–391 (1989).

    Article  CAS  Google Scholar 

  9. Hartley, S.B. et al. Elimination from peripheral lymphoid tissues of self-reactive B lymphocytes recognizing membrane-bound antigens. Nature 353, 765–769 (1991).

    Article  CAS  Google Scholar 

  10. Akkaraju, S., Canaan, K. & Goodnow, C.C. Self-reactive B cells are not eliminated or inactivated by autoantigen expressed on thyroid epithelial cells. J. Exp. Med. 186, 2005–2012 (1997).

    Article  CAS  Google Scholar 

  11. Cooke, M.P. et al. Immunoglobulin signal transduction guides the specificity of B cell-T cell interactions and is blocked in tolerant self-reactive B cells. J. Exp. Med. 179, 425–438 (1994).

    Article  CAS  Google Scholar 

  12. Healy, J.I. et al. Different nuclear signals are activated by the B cell receptor during positive versus negative signaling. Immunity 6, 419–428 (1997).

    Article  CAS  Google Scholar 

  13. Erickson, J.W., Posner, R.G., Goldstein, B., Holowka, D. & Baird, B. Bivalent ligand dissociation kinetics from receptor-bound immunoglobulin E: evidence for a time-dependent increase in ligand rebinding at the cell surface. Biochemistry 30, 2357–2363 (1991).

    Article  CAS  Google Scholar 

  14. Posner, R.G., Erickson, J.W., Holowka, D., Baird, B. & Goldstein, B. Dissociation kinetics of bivalent ligand-immunoglobulin E aggregates in solution. Biochemistry 30, 2348–2356 (1991).

    Article  CAS  Google Scholar 

  15. Sonoda, E. et al. B cell development under the condition of allelic inclusion. Immunity 6, 225–233 (1997).

    Article  CAS  Google Scholar 

  16. Borrero, M. & Clarke, S.H. Low-affinity anti-Smith antigen B cells are regulated by anergy as opposed to developmental arrest or differentiation to B-1. J. Immunol. 168, 13–21 (2002).

    Article  CAS  Google Scholar 

  17. Erikson, J. et al. Expression of anti-DNA immunoglobulin transgenes in non-autoimmune mice. Nature 349, 331–334 (1991).

    Article  CAS  Google Scholar 

  18. Lenschow, D.J. et al. Differential up-regulation of the B7–1 and B7–2 costimulatory molecules after Ig receptor engagement by antigen. J. Immunol. 153, 1990–1997 (1994).

    CAS  Google Scholar 

  19. Wither, J.E., Paterson, A.D. & Vukusic, B. Genetic dissection of B cell traits in New Zealand black mice. The expanded population of B cells expressing up-regulated costimulatory molecules shows linkage to Nba2. Eur. J. Immunol. 30, 356–365 (2000).

    Article  CAS  Google Scholar 

  20. Wither, J.E., Roy, V. & Brennan, L.A. Activated B cells express increased levels of costimulatory molecules in young autoimmune NZB and (NZB × NZW)F(1) mice. Clin. Immunol. 94, 51–63 (2000).

    Article  CAS  Google Scholar 

  21. Pike, B.L., Boyd, A.W. & Nossal, G.J. Clonal anergy: the universally anergic B lymphocyte. Proc. Natl. Acad. Sci. USA 79, 2013–2017 (1982).

    Article  CAS  Google Scholar 

  22. Fulcher, D.A. & Basten, A. Reduced life span of anergic self-reactive B cells in a double-transgenic model. J. Exp. Med. 179, 125–134 (1994).

    Article  CAS  Google Scholar 

  23. Harmon, J.M., Norman, M.R., Fowlkes, B.J. & Thompson, E.B. Dexamethasone induces irreversible G1 arrest and death of a human lymphoid cell line. J. Cell. Physiol. 98, 267–278 (1979).

    Article  CAS  Google Scholar 

  24. Thompson, J.S. et al. BAFF binds to the tumor necrosis factor receptor-like molecule B cell maturation antigen and is important for maintaining the peripheral B cell population. J. Exp. Med. 192, 129–135 (2000).

    Article  CAS  Google Scholar 

  25. Secrist, J.P., Burns, L.A., Karnitz, L., Koretzky, G.A. & Abraham, R.T. Stimulatory effects of the protein tyrosine phosphatase inhibitor, pervanadate, on T-cell activation events. J. Biol. Chem. 268, 5886–5893 (1993).

    CAS  PubMed  Google Scholar 

  26. Rathmell, J.C., Fournier, S., Weintraub, B.C., Allison, J.P. & Goodnow, C.C. Repression of B7.2 on self-reactive B cells is essential to prevent proliferation and allow Fas-mediated deletion by CD4+ T cells. J. Exp. Med. 188, 651–659 (1998).

    Article  CAS  Google Scholar 

  27. Goodnow, C.C., Brink, R. & Adams, E. Breakdown of self-tolerance in anergic B lymphocytes. Nature 352, 532–536 (1991).

    Article  CAS  Google Scholar 

  28. Vilen, B.J., Famiglietti, S.J., Carbone, A.M., Kay, B.K. & Cambier, J.C. B cell antigen receptor desensitization: disruption of receptor coupling to tyrosine kinase activation. J. Immunol. 159, 231–243 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Cook, M.C., Basten, A. & Fazekas de St Groth, B. Rescue of self-reactive B cells by provision of T cell help in vivo. Eur. J. Immunol. 28, 2549–2558 (1998).

    Article  CAS  Google Scholar 

  30. Lane, P. A molecular basis for T-dependent B cell activation. Behring Inst. Mitt. 96, 7–12 (1995).

    CAS  Google Scholar 

  31. Ding, L., Green, J.M., Thompson, C.B. & Shevach, E.M. B7/CD28-dependent and -independent induction of CD40 ligand expression. J. Immunol. 155, 5124–5132 (1995).

    CAS  PubMed  Google Scholar 

  32. Bretscher, P. & Cohn, M. A theory of self-nonself discrimination. Science 169, 1042–1049 (1970).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank K. Aviszus and L. Wysocki for Ars/A1 mice (for breeding), for ArsTyr and for input, and R. Pelanda for B1-8 mice (for breeding). Supported by the National Institutes of Health (R01-AI020519) and Nelson Family Fellowship for Pediatric Immunology from the National Jewish Medical and Research Center (S.B.G.).

Author information

Author notes

  1. Robert J Benschop

    Present address: Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, Indiana, 46285, USA

  2. Stephen B Gauld and Robert J Benschop: These authors contributed equally to this work.

Authors and Affiliations

  1. Integrated Department of Immunology, University of Colorado Health Sciences Center and National Jewish Medical and Research Center, Denver, 80206, Colorado, USA

    Stephen B Gauld, Robert J Benschop, Kevin T Merrell & John C Cambier

Authors
  1. Stephen B Gauld
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Robert J Benschop
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Kevin T Merrell
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. John C Cambier
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to John C Cambier.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Gauld, S., Benschop, R., Merrell, K. et al. Maintenance of B cell anergy requires constant antigen receptor occupancy and signaling. Nat Immunol 6, 1160–1167 (2005). https://doi.org/10.1038/ni1256

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ni1256

This article is cited by

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