Endogenous antigen tunes the responsiveness of naive B cells but not T cells.
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.
Division of Rheumatology, Department of Medicine, Rosalind Russell Medical Research Center for Arthritis, University of California, San Francisco, California 94143, USA.
Julie
J
Zikherman
Ramya
R
Parameswaran
Arthur
A
Weiss
D000818:Animals; D000941:Antigens / Q000276:immunology*; D001323:Autoantibodies / Q000276:immunology; D001324:Autoantigens / Q000276:immunology; D001327:Autoimmune Diseases / Q000276:immunology / Q000473:pathology; D001402:B-Lymphocytes / Q000166:cytology / Q000276:immunology*; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling; D017635:Clonal Anergy / Q000276:immunology; D015536:Down-Regulation; D017930:Genes, Reporter; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D007108:Immune Tolerance / Q000276:immunology*; D007072:Immunoglobulin D / Q000276:immunology; D007075:Immunoglobulin M / Q000276:immunology; D008213:Lymphocyte Activation / Q000276:immunology*; D051379:Mice; D018448:Models, Immunological; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1 / Q000235:genetics; D011947:Receptors, Antigen, B-Cell / Q000276:immunology / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology; D013154:Spleen / Q000166:cytology / Q000276:immunology; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology*; D019076:Transgenes / Q000235:genetics
D000941:Antigens; D001323:Autoantibodies; D001324:Autoantigens; D007072:Immunoglobulin D; D007075:Immunoglobulin M; C539818:Nr4a1 protein, mouse; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D011947:Receptors, Antigen, B-Cell; D049452:Green Fluorescent Proteins; D002118:Calcium