Graduate Student Researcher Univ. of Pittsburgh Sch. of Med. Pittsburgh, Pennsylvania, United States
Disclosure(s):
Luis J. Mena Hernandez, MD, MS: No financial relationships to disclose
Introduction/Rationale: 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.
