Uncovering a role of aryl hydrocarbon receptor (AhR) in the differentiation dynamics of human B cells 2258222

Abstract Introduction Upon activation, B cells differentiate into plasmablasts (PBs), germinal center (GC) B cells, and memory B cells (MBCs). Key transcription factors, including BACH2, IRF4, IRF8, PRDM1, and BCL6, play critical roles in regulating these distinct fates. Methods Using single-cell profiling, we identified the aryl hydrocarbon receptor (AhR) and its target genes as inducibly and differentially expressed in activated human B cells differentiating into pre-GC and PB populations. Additionally, by intersecting open chromatin regions with AhR chromatin immunoprecipitation sequencing datasets, we predicted AhR molecular activity in activated and pre-GC B cells. To investigate the function of AhR, we modulated its activity using agonist and antagonist ligands, as well as CRISPR editing, in the human B cell culture system. Results Activation of AhR with three different ligands (FICZ, Kynurenine, and TCDD) promoted PB generation, while AhR antagonism had the opposite effect. Furthermore, CRISPR editing revealed that FICZ-induced PB differentiation was AhR-dependent and could be further enhanced by knocking down GC-promoting transcription factors (IRF8, BATF, or PAX5). Multiome analysis reveals that AhR activation rapidly induces a PB gene expression module within activated B cells. Conclusion These findings identify AhR as a previously unrecognized regulator of human B cell fate dynamics and PB differentiation. This pathway represents a mechanism by which dietary, commensal, or environmental AhR ligands can modulate humoral B cell responses. These insights have broad implications for understanding vaccine efficacy and developing therapeutic strategies to enhance or suppress PB generation. Funding Source NHGRI UO1HG012041 NIAID R01AI170108 Topic Categories Immune Response Regulation: Molecular Mechanisms (IRM)