Endogenous antigen tunes the responsiveness of naive B cells but not T cells

Nature. 2012 Sep 6;489(7414):160-4. doi: 10.1038/nature11311.


In humans, up to 75% of newly generated B cells and about 30% of mature B cells show some degree of autoreactivity. Yet, how B cells establish and maintain tolerance in the face of autoantigen exposure during and after development is not certain. Studies of model B-cell antigen receptor (BCR) transgenic systems have highlighted the critical role of functional unresponsiveness or ‘anergy’. Unlike T cells, evidence suggests that receptor editing and anergy, rather than deletion, account for much of B-cell tolerance. However, it remains unclear whether the mature diverse B-cell repertoire of mice contains anergic autoreactive B cells, and if so, whether antigen was encountered during or after their development. By taking advantage of a reporter mouse in which BCR signalling rapidly and robustly induces green fluorescent protein expression under the control of the Nur77 regulatory region, antigen-dependent and antigen-independent BCR signalling events in vivo during B-cell maturation were visualized. Here we show that B cells encounter antigen during development in the spleen, and that this antigen exposure, in turn, tunes the responsiveness of BCR signalling in B cells at least partly by downmodulating expression of surface IgM but not IgD BCRs, and by modifying basal calcium levels. By contrast, no analogous process occurs in naive mature T cells. Our data demonstrate not only that autoreactive B cells persist in the mature repertoire, but that functional unresponsiveness or anergy exists in the mature B-cell repertoire along a continuum, a fact that has long been suspected, but never yet shown. These results have important implications for understanding how tolerance in T and B cells is differently imposed, and how these processes might go awry in disease.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigens / immunology*
  • Autoantibodies / immunology
  • Autoantigens / immunology
  • Autoimmune Diseases / immunology
  • Autoimmune Diseases / pathology
  • B-Lymphocytes / cytology
  • B-Lymphocytes / immunology*
  • Calcium / metabolism
  • Calcium Signaling
  • Clonal Anergy / immunology
  • Down-Regulation
  • Genes, Reporter
  • Green Fluorescent Proteins / genetics
  • Green Fluorescent Proteins / metabolism
  • Immune Tolerance / immunology*
  • Immunoglobulin D / immunology
  • Immunoglobulin M / immunology
  • Lymphocyte Activation / immunology*
  • Mice
  • Models, Immunological
  • Nuclear Receptor Subfamily 4, Group A, Member 1 / genetics
  • Receptors, Antigen, B-Cell / immunology
  • Receptors, Antigen, B-Cell / metabolism
  • Signal Transduction / immunology
  • Spleen / cytology
  • Spleen / immunology
  • T-Lymphocytes / cytology
  • T-Lymphocytes / immunology*
  • Transgenes / genetics


  • Antigens
  • Autoantibodies
  • Autoantigens
  • Immunoglobulin D
  • Immunoglobulin M
  • Nr4a1 protein, mouse
  • Nuclear Receptor Subfamily 4, Group A, Member 1
  • Receptors, Antigen, B-Cell
  • Green Fluorescent Proteins
  • Calcium