GEOapplication/xmlftp://ftp.ncbi.nlm.nih.gov/geo/series/GSE332nnn/GSE332886/primaryOK200TranscriptomicsMus musculusExpression profiling by high throughput sequencinghttps://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE332886GEOGSEfalseAire 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. Here, 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 may contribute to a lesser extent, at least under homeostatic conditions. While TLR-driven signals are sufficient in vitro to initiate PB differentiation from B1a and marginal zone B cells as previously described, we show that APRIL or BAFF synergize with TLR signaling to induce robust Aire expression, revealing a previously unrecognized TNF superfamily axis controlling Aire induction. Aire does not drive bona fide PGE in these cells, yet cell-intrinsically restrains their numbers, uncovering a role in homeostatic regulation of natural polyreactive IgM in steady state rather than classical maintenance of self-tolerance.2026/09/01GSE332886GSM9754609GSM9754608GSM9754612GSM9754611GSM9754603GSM9754614GSM9754613GSM9754602GSM9754616GSM9754605GSM9754615GSM9754604GSM9754607GSM9754606GSM975461016417332886Mus musculus