title: Intrinsic transcriptional heterogeneity in B cells controls early class switching to IgE.
abstract: Noncoding transcripts originating upstream of the immunoglobulin constant region (I transcripts) are required to direct activation-induced deaminase to initiate class switching in B cells. Differential regulation of Iε and Iγ1 transcription in response to interleukin 4 (IL-4), hence class switching to IgE and IgG1, is not fully understood. In this study, we combine novel mouse reporters and single-cell RNA sequencing to reveal the heterogeneity in IL-4-induced I transcription. We identify an early population of cells expressing Iε but not Iγ1 and demonstrate that early Iε transcription leads to switching to IgE and occurs at lower activation levels than Iγ1. Our results reveal how probabilistic transcription with a lower activation threshold for Iε directs the early choice of IgE versus IgG1, a key physiological response against parasitic infestations and a mediator of allergy and asthma.
authors.affiliation: Medical Research Council Laboratory of Molecular Biology, Cambridge CB2 0QH, England, UK.
authors.forename: Yee Ling
authors.initials: YL
authors.lastname: Wu
authors.affiliation: The Wellcome Trust Sanger Institute, Cambridge CB10 1SA, England, UK.
authors.forename: Michael J T
authors.identifier: 0000-0001-5924-3566
authors.initials: MJ
authors.lastname: Stubbington
authors.affiliation: Medical Research Council Laboratory of Molecular Biology, Cambridge CB2 0QH, England, UK.
authors.forename: Maria
authors.identifier: 0000-0001-8142-3053
authors.initials: M
authors.lastname: Daly
authors.affiliation: The Wellcome Trust Sanger Institute, Cambridge CB10 1SA, England, UK.
authors.forename: Sarah A
authors.initials: SA
authors.lastname: Teichmann
authors.affiliation: Medical Research Council Laboratory of Molecular Biology, Cambridge CB2 0QH, England, UK car@mrc-lmb.cam.ac.uk.
authors.forename: Cristina
authors.identifier: 0000-0003-4898-5550
authors.initials: C
authors.lastname: Rada
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000378:metabolism*; D003564:Cytidine Deaminase / Q000502:physiology; D017578:Immunoglobulin Class Switching; D007073:Immunoglobulin E / Q000235:genetics*; D015847:Interleukin-4 / Q000097:blood; D051379:Mice; D008807:Mice, Inbred BALB C; D011401:Promoter Regions, Genetic; D014158:Transcription, Genetic; D000098830:AICDA (Activation-Induced Cytidine Deaminase)
chemical_list: D015847:Interleukin-4; D007073:Immunoglobulin E; D000098830:AICDA (Activation-Induced Cytidine Deaminase); D003564:Cytidine Deaminase