Context-dependent regulation of Th17-associated genes and IFNγ expression by the transcription factor NFAT5

Stress-activated transcription factors influence T-cell function in different physiopathologic contexts. NFAT5, a relative of nuclear factor κB and the calcineurin-activated NFATc transcription factors, protects mammalian cells from hyperosmotic stress caused by the elevation of extracellular sodium levels. In T cells exposed to hypernatremia, NFAT5 not only induces osmoprotective gene products but also cytokines and immune receptors, which raises the question of whether this factor could regulate other T-cell functions in osmostress-independent contexts. Here we have used mice with a conditional deletion of Nfat5 in mature T lymphocytes to explore osmostress-dependent and -independent functions of this factor. In vitro experiments with CD4 T cells stimulated in hyperosmotic medium showed that NFAT5 enhanced the expression of IL-2 and the Th17-associated gene products RORγt and IL-23R. By contrast, NFAT5-deficient CD4 T cells activated in vivo by anti-CD3 antibody exhibited a different activation profile and were skewed towards enhanced interferon γ (IFNγ) and IL-17 expression and attenuated Treg responses. Using a model of experimental colitis, we observed that mice lacking NFAT5 in T cells exhibited exacerbated intestinal colitis and enhanced expression of IFNγ in draining lymph nodes and colon. These results show that NFAT5 can modulate different T-cell responses depending on stress conditions and stimulatory context.JA was funded by the Spanish Ministry of Economy and Competitiveness (SAF2011-24268, cofunded by the European Regional Development Fund), and Fundació la Marató TV3 (122530). CL-R was funded by the Spanish Ministry of Economy and Competitiveness (SAF2012-36535, SAF2015-71363-R, cofunded by the European Regional Development Fund). CL-R is a recipient of an ICREA Acadèmia award from Institució Catalana de Recerca i Estudis Avançats (ICREA, Generalitat de Catalunya). JA and CL-R also acknowledge funding support from Generalitat de Catalunya (2009SGR601, 2014SGR1153) and the Spanish Ministry of Economy and Competitiveness, through the 'María de Maeztu' Program for Units of Excellence in R&D (MDM-2014-0370). RM was funded by the Spanish Ministry of Economy and Competitiveness (SAF2011-22463 and SAF2014-55088-R, cofunded by the European Regional Development Fund). MA was supported by predoctoral fellowships from Generalitat de Catalunya (FI-DGR program 2009) and the Spanish Ministry of Education, Culture and Sports (FPU program, AP2010-5411). MI was partially supported by a grant from the Spanish Ministry of Economy and Competitiveness (IPT2011-1527-010000). ST is the recipient of a predoctoral fellowship of the Spanish Ministry of Economy and Competitiveness (BES-2013-062670)