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 defined. We examined IgH isotypespecific BCR function by analyzing naturally switched B cells from wild-type mice, as well as by engineering polyclonal Igh gamma 1/gamma 1 and Igh epsilon/epsilon 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 Igh gamma 1/gamma 1 and Igh epsilon/epsilon 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 mIg mu > mIg gamma 1 > mIg epsilon, and that these BCR expression differences influence respective developmental fitness. Restrained B cell development from Igh gamma 1/gamma 1 and Igh epsilon/epsilon 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.