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

The autoimmune regulator (Aire) promotes T cell tolerance through promiscuous gene expression in medullary thymic epithelial cells, but growing evidence points to additional roles beyond thymic tolerance. We show that antibody-secreting cells (ASCs) in the spleen and bone marrow expressed Aire, with highest expression in immunoglobulin M (IgM)+ cells. These Aire+IgM+ cells displayed hallmarks of natural IgM-secreting cells: they were T cell independent, exhibited distinct repertoire features, and arose primarily from B-1a and marginal zone B cells. While innate signals were sufficient in vitro to promote plasmablast differentiation, synergistic B cell survival and growth factor signaling through B cell-activating factor (BAFF) or APRIL was required to robustly induce Aire, revealing a previously unrecognized tumor necrosis factor (TNF) superfamily pathway controlling Aire induction. Aire did not promote promiscuous gene expression in these cells, but intrinsically limited their numbers, identifying a role in homeostatic regulation of natural polyreactive IgM in steady state rather than self-tolerance.