IRF7-Dependent IFN-β Production in Response to RANKL Promotes Medullary Thymic Epithelial Cell Development

The contributions of IFN regulatory factor (IRF) 3/7 and the type I IFNs IFN-alpha/beta to the innate host defense have been extensively investigated; however, their role in thymic development is less clear. In this study, we show that mice lacking the type I IFN receptor IFN-alpha/beta receptor (IFNAR) or the downstream transcription factor STAT1 harbor a significant reduction in self-Ag-presenting, autoimmune regulator (AIRE)(+) medullary thymic epithelial cells (mTECs). Constitutive IFNAR signaling occurs in the thymic medulla in the absence of infection or inflammation. Receptor activator for NF-kappa B (RANK) ligand stimulation results in IFN-beta upregulation, which in turn inhibits RANK signaling and facilitates AIRE expression in mTECs. Finally, we find that IRF7 is required for thymic IFN-beta induction, maintenance of thymic architecture, and mTEC differentiation. We conclude that spatially and temporally coordinated cross talks between the RANK ligand/RANK and IRF7/IFN-beta/IFNAR/STAT1 pathways are essential for differentiation of AIRE(+) mTECs. The Journal of Immunology, 2013, 190: 3289-3298.