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

Nature 2012 Sep;489(7414):160-4

Division of Rheumatology, Department of Medicine, Rosalind Russell Medical Research Center for Arthritis, University of California, San Francisco, California 94143, USA.

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.

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http://dx.doi.org/10.1038/nature11311DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3438375PMC
September 2012
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References

(Supplied by CrossRef)

H Wardemann et al.
Science 2003

CC Goodnow et al.
Nature 1988

JC Cambier et al.
Nature Rev. Immunol. 2007

J Lang et al.
J. Exp. Med. 1997

R Halverson et al.
Nature Immunol. 2004

AE Moran et al.
J. Exp. Med. 2011

A Winoto et al.
Cell 2002

PR Mittelstadt et al.
J. Immunol. 1993

J Zikherman et al.
Immunity 2010

RR Hardy et al.
J. Exp. Med. 1991

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