Intrinsic transcriptional heterogeneity in B cells controls early class switching to IgE

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 I epsilon and I gamma 1 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 I epsilon but not I gamma 1 and demonstrate that early I epsilon transcription leads to switching to IgE and occurs at lower activation levels than I gamma 1. Our results reveal how probabilistic transcription with a lower activation threshold for I epsilon directs the early choice of IgE versus IgG1, a key physiological response against parasitic infestations and a mediator of allergy and asthma.