Antibody-secreting cell destiny emerges during the initial stages of B-cell activation

• Type of Material: Article
• Authors: Christopher Scharer, Emory University; Dillon G. Patterson, Emory University; Tian Mi, Emory University; Madeline J. Price, Emory University; Sakeenah L. Hicks, Emory University; Jeremy Boss, Emory University
• Language: English
• Date: 2020-08-10
• Publisher: Nature Portfolio
• Publication Version: Final Published Version
• Copyright Statement: © The Author(s) 2020
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1038/s41467-020-17798-x
• Title of Journal or Parent Work: Nature Communications
• Volume: 11
• Issue: 1
• Start Page: 3989
• End Page: 3989
• Grant/Funding Information: This work was supported by P01 AI125180 to J.M.B., RO1 AI123733 to J.M.B., and F31 AI138391 to M.J.P.; Myd88-deficient mice were a gift from Dr. Rheinallt Jones.
• Keywords: Division; Generation; Transcription factor; Germinal center B; Blimp-1; Differentiation; Plasma cells; L-selectin; Science & Technology; Gene expression; Multidisciplinary Sciences; Science & Technology - Other Topics; Fates
• Research Categories: Biology, Cell; Health Sciences, Immunology; Biology, Microbiology

Abstract

Upon stimulation, B cells assume heterogeneous cell fates, with only a fraction differentiating into antibody-secreting cells (ASC). Here we investigate B cell fate programming and heterogeneity during ASC differentiation using T cell-independent models. We find that maximal ASC induction requires at least eight cell divisions in vivo, with BLIMP-1 being required for differentiation at division eight. Single cell RNA-sequencing of activated B cells and construction of differentiation trajectories reveal an early cell fate bifurcation. The ASC-destined branch requires induction of IRF4, MYC-target genes, and oxidative phosphorylation, with the loss of CD62L expression serving as a potential early marker of ASC fate commitment. Meanwhile, the non-ASC branch expresses an inflammatory signature, and maintains B cell fate programming. Finally, ASC can be further subseted based on their differential responses to ER-stress, indicating multiple development branch points. Our data thus define the cell division kinetics of B cell differentiation in vivo, and identify the molecular trajectories of B cell fate and ASC formation.