GEOapplication/xmlftp://ftp.ncbi.nlm.nih.gov/geo/series/GSE310nnn/GSE310317/primaryOK200TranscriptomicsMus musculusExpression profiling by high throughput sequencinghttps://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE310317GEOGSEfalseAire is a cell intrinsic regulator of natural IgM-secreting cellsThe Autoimmune Regulator (Aire) serves an essential role in T cell tolerance by promoting ‘promiscuous gene expression’ (PGE) in medullary thymic epithelial cells (mTECs). Several disease manifestations associated with Aire-deficiency, some apparently non-autoimmune, along with Aire expression beyond mTECs, suggest that Aire may regulate additional physiological processes. We show that plasmablasts (PBs) and plasma cells (PCs) constitute a principal Aire-expressing population in the spleen, with highest expression in IgM+ cells and lower levels in class-switched PB/PCs. The Aire+IgM+ PB/PC compartment exhibits typical hallmarks of natural IgM secreting cells of extrafollicular origin: it is T cell-independent, exhibits distinct BCR features, and can originate from both peritoneal B1a cells and splenic marginal zone B cells, whereas follicular B cells contribute minimally. While TLR-driven signals initiate PB differentiation as previously described, we find that subsequent stimulation through APRIL or BAFF - but not RANK or CD40 - induces Aire expression, uncovering a novel TNF superfamily axis upstream of Aire induction. Aire does not drive bona fide PGE in these cells, yet cell-intrinsically restrains their numbers, limiting steady-state serum levels of polyreactive IgM. These findings identify Aire as a B lineage-intrinsic regulator of natural IgM, raising the possibility that dysregulation of the IgM+ PB/PC compartment contributes to the pathological consequences of Aire-deficiency.2026/08/31GSE310317GSM9293948GSM9293947GSM9293949GSM9293951GSM9293950GSM929395219057310317Mus musculus