Type I interferon (IFN-I) provides effective antiviral immunity but can exacerbate harmful inflammatory reactions and cause hematopoietic stem cell (HSC) exhaustion; therefore, IFN-I expression must be tightly controlled. While signaling mechanisms that limit IFN-I induction and function have been extensively studied, less is known about transcriptional repressors acting directly on IFN-I regulatory regions. We show that NFAT5, an activator of macrophage pro-inflammatory responses, represses Toll-like receptor 3 and virus-induced expression of IFN-I in macrophages and dendritic cells. Mice lacking NFAT5 exhibit increased IFN-I production and better control of viral burden upon LCMV infection but show exacerbated HSC activation under systemic poly(I:C)-induced inflammation. We identify IFNβ as a primary target repressed by NFAT5, which opposes the master IFN-I inducer IRF3 by binding to an evolutionarily conserved sequence in the IFNB1 enhanceosome that overlaps a key IRF site. These findings illustrate how IFN-I responses are balanced by simultaneously opposing transcription factors.

This work was supported by the Agencia Estatal de Investigación, Spanish Ministry of Economy and Competitiveness, and FEDER (SAF2015-71363-R and RTI2018-095902-B-I00 to C. López-Rodríguez and J. Aramburu; and SAF2016-75505-R to A. Meyerhans and J. Argilaguet), and Fundació la Marató TV3 (1225-30 and 201619-30) to C. López-Rodríguez and J. Aramburu. We also acknowledge funding support from Generalitat de Catalunya (2014SGR1153 and 2017SGR888) and the Spanish Ministry of Economy and Competitiveness through the “María de Maeztu” Program for Units of Excellence in R&D (MDM2014-0370). H. Huerga Encabo was supported by a predoctoral fellowship of the Spanish Ministry of Education, Culture and Sports (FPU13/01798), and L. Traveset was supported by a predoctoral fellowship of the Spanish Ministerio de Economy, Industry and Competitiveness (BES-2015-074170). C. LópezRodríguez is a recipient of an ICREA Acadèmia award from Institució Catalana de Recerca i Estudis Avançats (Generalitat de Catalunya)