CRISPR/Cas9 editing reveals IRF8 regulated gene signatures restraining plasmablast differentiation

• Authors: Zhihong Zuo, Emory University; Anna K Kania, Emory University; Dillon G Patterson, Emory University; Sakeenah L Hicks, Emory University; Jeffrey Maurer, Emory University; Mansi Gupta, Emory University; Jeremy M Boss, Emory University; Christopher D Scharer, Emory University
• Journal Title: HELIYON
• Volume: Volume 9, Number 6
• Publisher: CELL PRESS | 2023-06-01, Pages e17527-e17527
• Type of Work: Article | Final Publisher PDF
• Publisher DOI: http://doi.org/10.1016/j.heliyon.2023.e17527
• Subjects: Biology, Microbiology; Health Sciences, Immunology; Biology, General; Biology, Cell
• Keywords: Science & Technology; Multidisciplinary Sciences; Science & Technology - Other Topics; CRISPR; Cas9; Cas9 ribonucleoprotein; Gene editing; Hematopoietic stem cells; Primary mouse B cells; IRF8; TRANSCRIPTION FACTORS IRF8; B-CELL DEVELOPMENT; TARGET GENES; EXPRESSION; PU.1; IDENTIFICATION; EFFICIENT; IMMUNITY; ELEMENTS; PROGRAM

Abstract

The transcription factor Interferon regulatory factor 8 (IRF8) is involved in maintaining B cell identity. However, how IRF8 regulates T cell independent B cell responses are not fully characterized. Here, an in vivo CRISPR/Cas9 system was optimized to generate Irf8-deficient murine B cells and used to determine the role of IRF8 in B cells responding to LPS stimulation. Irf8-deficient B cells more readily formed CD138+ plasmablasts in response to LPS with the principal dysregulation occurring at the activated B cell stage. Transcriptional profiling revealed an upregulation of plasma cell associated genes prematurely in activated B cells and a failure to repress the gene expression programs of IRF1 and IRF7 in Irf8-deficient cells. These data expand on the known roles of IRF8 in regulating B cell identity by preventing premature plasma cell formation and highlight how IRF8 helps evolve TLR responses away from the initial activation towards those driving humoral immunity.