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

Abstract

Mature B cells encounter antigens during development that induce anergy or functional unresponsiveness; this large reservoir of dormant autoreactive B cells may serve as a pool of extended antibody specificity for purposes of protective immunity, as well as the source of pathogenic autoantibodies that characterize rheumatic diseases such as systemic lupus erythematosus. This study demonstrates that B cells encounter autoantigens during development and that autoreactive B cells persist in the mature repertoire, but become less responsive or anergic to B-cell antigen-receptor stimulation, thereby avoiding autoimmunity. Autoreactivity seems to correlate with the threshold of B-cell activation so that only foreign antigens interacting with B cells at a level greater than the cells' inherent autoreactivity will be activated. The authors speculate that this large reservoir of dormant autoreactive B cells may act as a source of pathogenic autoantibodies in rheumatic diseases such as systemic lupus erythematosus. In humans, up to 75% of newly generated B cells and about 30% of mature B cells show some degree of autoreactivity1. 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’2,3. Unlike T cells, evidence suggests that receptor editing and anergy, rather than deletion, account for much of B-cell tolerance4,5. 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.