IgH isotype-specific B cell receptor expression influences B cell fate

Abstract

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 γ1/γ1 andε/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 γ1/γ1 andε/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 γ1/γ1 andε/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.

B Cell Intrinsic Mechanisms Constraining IgE Memory

“…A new mouse model has been generated to force membrane IgE expression from early B cell development ( 105 ), similarly to εKI mice (Figure 2 ), but using a different strategy and a mouse Cε gene. These animals have also a strong blockade at the pro-B cell stage, again showing that Cε gene cannot support B cell development.…”

Memory control by the B cell antigen receptor

“…Furthermore, when interpreting the data regarding the antigen‐independent function of murine mIgE‐BCRs, one has to consider that all in vitro experiments in these studies were done with exogenously expressed mIgE and hence the amounts of cell surface mIgE that were achieved in these experiments did not necessarily match those observed in native cells. This fact may be important, since a recent study, which compared the tonic (ie, antigen‐independent) signaling capacities of different mIg isotypes in mouse model systems, reported that the expression of mIgE from the endogenous Ig ε heavy chain locus with all its regulatory genetic elements leads to a very low expression of mIgE‐BCRs on the cell surface, much lower than that of mIgM‐ and mIgG‐containing BCRs . This low abundance of cell surface‐expressed mIgE‐BCRs was associated with poor survival of the cells, which most likely was caused by an insufficient tonic mIgE‐BCR maintenance signal.…”

IL-21 is a broad negative regulator of IgE class switch recombination in mouse and human B cells

“…The majority of IgE + B cells were found to differentiate into PCs that were primarily short-lived ( Yang et al, 2014 ). The various distinct features of IgE responses have been attributed to unique properties of the IgE B cell receptor (BCR; Achatz-Straussberger et al, 2008 ; Haniuda et al, 2016 ; Laffleur et al, 2015 ; Tong et al, 2017 ; Vanshylla et al, 2018 ; Yang et al, 2016 ).…”