Multimerizing transcription factors FOXP3 and AIRE as chromatin architectural regulators

Central and peripheral immune tolerance depend on distinct transcriptional programs orchestrated by autoimmune regulator (AIRE) and FOXP3, respectively. AIRE promotes the expression of peripheral tissue antigens in medullary thymic epithelial cells for negative selection of autoreactive T cells, whereas FOXP3 enforces the immune-suppressive program of regulatory T cells. Although their immunological roles are well established, the molecular mechanisms by which AIRE and FOXP3 engage the genome and regulate transcription have long been unclear. Recent structural, biochemical and genomic work has revealed an unexpected shared principle: both FOXP3 and AIRE form homomultimers that function as chromatin organizers. Despite functioning in different immunological contexts and possessing distinct modes of genome interaction, both proteins leverage and reinforce pre-existing chromatin landscapes to coordinate broader gene expression programs. In this Review, we summarize recent advances and emerging mechanistic insights into FOXP3 and AIRE, focusing on their multimerization, interactions with repetitive DNA and enhancers and roles as architectural regulators that shape transcriptional programs essential for immune tolerance.