AIRE's Complex Role Beyond Promiscuous Gene Expression

Central tolerance, established in the thymus, ensures T cells are nonreactive to self-antigens while maintaining a functional immune repertoire. Medullary thymic epithelial cells (mTECs) and thymic dendritic cells (DCs) play a crucial role in this mechanism by orchestrating the selection and deletion of autoreactive thymocytes, a process heavily influenced by the Autoimmune Regulator (AIRE). AIRE promotes the promiscuous expression of tissue-restricted antigens (TRAs) in mTECs, enabling the elimination of self-reactive T cells and the differentiation of regulatory T cells (Tregs). Studies on the role of AIRE in transcriptional regulation and nuclear body localization have significantly advanced our understanding of its mechanisms, revealing protein interactions with chromatin-associated complexes that facilitate broad transcriptomic complexity in mTECs. However, the discovery of neutralizing type 1 interferon (T1 IFN) autoantibodies in APECED patients, alongside recently identified AIRE-induced IFN signals in the thymus, suggests that AIRE's influence extends beyond its classical function in negative selection, potentially playing a broader role in thymic homeostasis via inflammatory signals. This review discusses recent advances in understanding AIRE's complexity, its role in transcriptional regulation and nuclear location, insights from studies in human APECED patients and rodent models, and the emerging concept of an IFN-mediated tonic inflammatory signal in the thymus.