MHCII in antigen-presenting cells (APCs) is a key regulator of adaptive immune responses. Expression of MHCII genes is controlled by the transcription coactivator CIITA, itself regulated through cell type-specific promoters. Here we show that the transcription factor NFAT5 is needed for expression of Ciita and MHCII in macrophages, but not in dendritic cells and other APCs. NFAT5-deficient macrophages showed defective activation of MHCII-dependent responses in CD4+ T lymphocytes and attenuated capacity to elicit graft rejection in vivo. Ultrasequencing analysis of NFAT5-immunoprecipitated chromatin uncovered an NFAT5-regulated region distally upstream of Ciita This region was required for CIITA and hence MHCII expression, exhibited NFAT5-dependent characteristics of active enhancers such as H3K27 acetylation marks, and required NFAT5 to interact with Ciita myeloid promoter I. Our results uncover an NFAT5-regulated mechanism that maintains CIITA and MHCII expression in macrophages and thus modulates their T lymphocyte priming capacity.

This work was supported by the Spanish Ministry of Economy and Competitiveness (MINECO), Agencia Estatal de Investigación, and European Regional Development Fund (SAF2012-36535, SAF2015-71363-R, and BFU2016-77961-P), and Fundació la Marató de TV3 (1225-30 and 201619-30). We also acknowledge funding support from Generalitat de Catalunya (2014SGR1153, 2017SGR888, and 2017SGR702) and MINECO through the “Unidad de Excelencia María de Maeztu” funded by MINECO (MDM-2014-0370). H. Huerga Encabo was supported by a predoctoral fellowship of the Spanish Ministerio de Educación, Cultura y Deporte (FPU13/01798). M. Tellechea was supported by fellowships from Fundació Catalunya-La Pedrera (2011) and Generalitat de Catalunya (FI-DGR program 2013). C. López-Rodríguez is a recipient of an ICREA Acadèmia award from Institució Catalana de Recerca i Estudis Avançats (ICREA, Generalitat de Catalunya).