title: IRF7-dependent IFN-β production in response to RANKL promotes medullary thymic epithelial cell development.
abstract: The contributions of IFN regulatory factor (IRF) 3/7 and the type I IFNs IFN-α/β 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-α/β 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-κB (RANK) ligand stimulation results in IFN-β upregulation, which in turn inhibits RANK signaling and facilitates AIRE expression in mTECs. Finally, we find that IRF7 is required for thymic IFN-β 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-β/IFNAR/STAT1 pathways are essential for differentiation of AIRE(+) mTECs.
authors: Division of Biological Sciences, University of California, San Diego, La Jolla, CA 92093, USA.
authors: Dennis C
authors: DC
authors: Otero
authors: Darren P
authors: DP
authors: Baker
authors: Michael
authors: M
authors: David
mesh_terms: D000818:Animals; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism*; D050839:Interferon Regulatory Factor-7 / Q000235:genetics* / Q000378:metabolism; D016899:Interferon-beta / Q000096:biosynthesis*; D051379:Mice; D018345:Mice, Knockout; D053245:RANK Ligand / Q000494:pharmacology*; D053246:Receptor Activator of Nuclear Factor-kappa B / Q000378:metabolism; D053633:Receptor, Interferon alpha-beta / Q000235:genetics / Q000378:metabolism; D050794:STAT1 Transcription Factor / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D017154:Stromal Cells / Q000187:drug effects / Q000378:metabolism; D013950:Thymus Gland / Q000187:drug effects / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism; D044763:Ubiquitin-Conjugating Enzymes / Q000378:metabolism; D000096927:AIRE Protein
chemical_list: D050839:Interferon Regulatory Factor-7; D016899:Interferon-beta; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; D053633:Receptor, Interferon alpha-beta; D050794:STAT1 Transcription Factor; D014157:Transcription Factors; D044763:Ubiquitin-Conjugating Enzymes; D000096927:AIRE Protein; C508032:Ifnar1 protein, mouse