Aire is a cell intrinsic regulator of natural IgM-secreting cells

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.