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

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 114; no. 40; pp. E8411 - E8420
• Main Authors: Tong, Pei, Granato, Alessandra, Zuo, Teng, Chaudhary, Neha, Zuiani, Adam, Han, Seung Seok, Donthula, Rakesh, Shrestha, Akritee, Sen, Debattama, Magee, Jennifer M., Gallagher, Michael P., van der Poel, Cees E., Carroll, Michael C., Wesemann, Duane R.
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 03.10.2017
• Series: PNAS Plus
• Subjects: Alternative splicing; Antibodies; B-cell receptor; Biological Sciences; Cell fate; Cells; Developmental stages; Fitness; Genomics; Heavy chains; Immunoglobulin E; Immunoglobulin G; Immunoglobulin M; Immunoglobulins; Immunological memory; Isotypes; Lymphocytes B; Memory cells; Mice; PNAS Plus; Receptor mechanisms; Receptors; Ribonucleic acid; RNA; Rodents; Signal strength; Splicing; BCR; B cell; antibody; memory; IgE
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1704962114

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.