IgG1 memory B cells keep the memory of IgE responses

Jin-Shu He,Josephine Lum,Vipin Narang,Sharrada Subramaniam,Sean P Saunders,Andrea Lee,Kandhadayar Srinivasan,Jinmiao Chen,Nur Hidayah Hamadee,Maria A Curotto De Lafaille,Tsao Wen-Shan,Juan J Lafaille,Michael Poidinger,Francesca Zolezzi,Daniel Carbajo

doi:10.1038/s41467-017-00723-0

Abstract

The unique differentiation of IgE cells suggests unconventional mechanisms of IgE memory. IgE germinal centre cells are transient, most IgE cells are plasma cells, and high affinity IgE is produced by the switching of IgG1 cells to IgE. Here we investigate the function of subsets of IgG1 memory B cells in IgE production and find that two subsets of IgG1 memory B cells, CD80+CD73+ and CD80−CD73−, contribute distinctively to the repertoires of high affinity pathogenic IgE and low affinity non-pathogenic IgE. Furthermore, repertoire analysis indicates that high affinity IgE and IgG1 plasma cells differentiate from rare CD80+CD73+ high affinity memory clones without undergoing further mutagenesis. By identifying the cellular origin of high affinity IgE and the clonal selection of high affinity memory B cells into the plasma cell fate, our findings provide fundamental insights into the pathogenesis of allergies, and on the mechanisms of antibody production in memory B cell responses.

Highlights

The unique differentiation of IgE cells suggests unconventional mechanisms of IgE memory
We found that the IgG1 memory B cells (MBC) subset with a phenotype that is ‘pro-plasma cells (PC)’ gives rise to an early burst of high affinity IgE that mediates anphylaxis, while another ‘pro-germinal centre (GC)’ subset generates a late, low affinity and non-pathogenic IgE response
The functional analysis and RNA sequencing (RNA-seq) expression data of IgG1 MBC subsets in our work indicate that the double positive (DP) IgG1 MBC are mainly ‘pro-PC’ cells, while the double negative (DN) IgG1 MBC are ‘pro-GC’ cells

Summary

Results

CD80+CD73+ IgG1 MBC generate high affinity IgE PC. The ability of subsets of mouse IgG1 MBC to give rise to IgE-secreting cells was analysed using well characterised models of type 2 a. Similar results were obtained when CD73+ IgG1 MBC (corresponding to DP IgG1 MBC) and CD73− IgG1 MBC (corresponding to SP plus DN IgG1 MBC) from OVA-PEP1 immunised TBmc mice were adoptively transferred into wild-type (WT) BALB/c mice (Supplementary Fig. 3b) These results demonstrate that CD73+ DP IgG1 MBC are the precursors of IgE cells producing high affinity IgE in memory responses, while SP and DN IgG1 MBC give rise to a late, low affinity IgE response. To determine the fate of IgE cells derived from each IgG1 memory subset, we analysed progeny cells by flow cytometry using the TBmc OVA-PEP1 immunisation system (Fig. 2a). IgG1 and IgE PC, GC and MBC in the spleens of recipient mice were quantified 1 and 6 weeks post secondary immunisation by flow cytometry analysis (Fig. 5a, b, and Supplementary Fig. 9a for gating strategy, T cell only and non-transferred controls). The results demonstrate that IgE derived from DP IgG1 MBC is of high affinity and pathogenic, while IgE derived from DN IgG1 MBC is of low affinity and does not contribute to anaphylaxis

Discussion

50 IgG1 DN

Methods