IgH isotype-specific B cell receptor expression influences B cell fate
Ig heavy chain (IgH) isotypes (e.g., IgM, IgG, and IgE) are generated as secreted/soluble antibodies (sIg) or as membrane-bound (mIg) B cell receptors (BCRs) through alternative RNA splicing. IgH isotype dictates soluble antibody function, but how mIg isotype influences B cell behavior is not well d...
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Published in | Proceedings of the National Academy of Sciences - PNAS Vol. 114; no. 40; pp. E8411 - E8420 |
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Main Authors | , , , , , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
United States
National Academy of Sciences
03.10.2017
|
Series | PNAS Plus |
Subjects | |
Online Access | Get full text |
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Summary: | Ig heavy chain (IgH) isotypes (e.g., IgM, IgG, and IgE) are generated as secreted/soluble antibodies (sIg) or as membrane-bound (mIg) B cell receptors (BCRs) through alternative RNA splicing. IgH isotype dictates soluble antibody function, but how mIg isotype influences B cell behavior is not well defined. We examined IgH isotype-specific BCR function by analyzing naturally switched B cells from wild-type mice, as well as by engineering polyclonal Ighγ1/γ1 and Ighε/ε mice, which initially produce IgG1 or IgE from their respective native genomic configurations. We found that B cells from wild-type mice, as well as Ighγ1/γ1 and Ighε/ε mice, produce transcripts that generate IgM, IgG1, and IgE in an alternative splice form bias hierarchy, regardless of cell stage. In this regard, we found that mIgμ > mIgγ1 > mIgε, and that these BCR expression differences influence respective developmental fitness. Restrained B cell development from Ighγ1/γ1 and Ighε/ε mice was proportional to sIg/mIg ratios and was rescued by enforced expression of the respective mIgs. In addition, artificially enhancing BCR signal strength permitted IgE⁺ memory B cells—which essentially do not exist under normal conditions—to provide long-lived memory function, suggesting that quantitative BCR signal weakness contributes to restraint of IgE B cell responses. Our results indicate that IgH isotype-specific mIg/BCR dosage may play a larger role in B cell fate than previously anticipated. |
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Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Author contributions: P.T., A.G., T.Z., and D.R.W. designed research; P.T., A.G., T.Z., A.Z., S.S.H., R.D., A.S., D.S., J.M.M., and M.P.G. performed research; C.E.v.d.P. and M.C.C. contributed new reagents/analytic tools; P.T., A.G., T.Z., N.C., A.Z., S.S.H., D.S., and D.R.W. analyzed data; P.T., A.G., and D.R.W. wrote the paper; and D.R.W. conceptualized the study. 1P.T. and A.G. contributed equally to this work. Edited by Klaus Rajewsky, Max Delbrück Center for Molecular Medicine, Berlin, Germany, and approved August 16, 2017 (received for review March 28, 2017) |
ISSN: | 0027-8424 1091-6490 |
DOI: | 10.1073/pnas.1704962114 |