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

Proc Natl Acad Sci U S A. 2017 Oct 3;114(40):E8411-E8420. doi: 10.1073/pnas.1704962114. Epub 2017 Sep 18.

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 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.

Keywords: B cell; BCR; IgE; antibody; memory.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • B-Lymphocytes / cytology
  • B-Lymphocytes / physiology*
  • Female
  • Gene Expression Profiling
  • Immunoglobulin Class Switching*
  • Immunoglobulin E / genetics
  • Immunoglobulin E / metabolism*
  • Immunoglobulin G / genetics
  • Immunoglobulin G / metabolism*
  • Immunoglobulin Heavy Chains / genetics
  • Immunoglobulin Heavy Chains / metabolism*
  • Immunoglobulin M / genetics
  • Immunoglobulin M / metabolism*
  • Male
  • Mice
  • Receptors, Antigen, B-Cell / metabolism*

Substances

  • Immunoglobulin G
  • Immunoglobulin Heavy Chains
  • Immunoglobulin M
  • Receptors, Antigen, B-Cell
  • Immunoglobulin E