Isotype-specific antibody secreting plasma cells harbor epigenetic and transcription factor architectures defining distinct cell lineages.

Antibody-secreting cells (ASCs) are critical effectors of humoral immunity, wherein their distinct isotypes play specialized roles in pathogen defense. Despite studies defining the transcriptional programs of selected ASC isotypes, specific mechanisms underlying isotype-specific gene regulation are largely unaddressed. Here, we performed an integrated multiomics analysis (RNA sequencing, ATAC-seq [assay for transposase-accessible chromatin using sequencing], DNA methylation) on surface-sorted IgM, IgG, and IgA ASCs isolated from the spleens and mediastinal lymph nodes of mice following influenza infection. Although conclusions regarding temporal and spatial specific programs could not be determined, we observed isotype-enriched expression patterns mapping to TLR signaling, cell cycle, cholesterol metabolism, cell adhesion, and homing. ETS:IRF, NFAT, REL, RUNX, SMAD, and STAT5 binding motifs differentially mapped to isotype-enriched gene expression programs. Additionally, DNA hypomethylation patterns in class-switched ASCs correlate with transcription factor-specific programming. The unique transcriptional and epigenetic programs among the 3 ASC isotypes suggest that each is a distinct lineage that dictates isotype-specific functional characteristics important for humoral immunity.