title: Context-dependent regulation of Th17-associated genes and IFNγ expression by the transcription factor NFAT5.
abstract: 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.
authors.affiliation: Department of Experimental and Health Sciences, Universitat Pompeu Fabra, Barcelona, Spain.
authors.forename: Maria
authors.initials: M
authors.lastname: Alberdi
authors.affiliation: Institute of Biomedicine and Biotechnology of Cantabria (IBBTEC CSIC-Universidad de Cantabria), Santander, Spain.
authors.forename: Marcos
authors.initials: M
authors.lastname: Iglesias
authors.affiliation: Department of Experimental and Health Sciences, Universitat Pompeu Fabra, Barcelona, Spain.
authors.forename: Sonia
authors.initials: S
authors.lastname: Tejedor
authors.affiliation: Institute of Biomedicine and Biotechnology of Cantabria (IBBTEC CSIC-Universidad de Cantabria), Santander, Spain.
authors.forename: Ramón
authors.initials: R
authors.lastname: Merino
authors.affiliation: Department of Experimental and Health Sciences, Universitat Pompeu Fabra, Barcelona, Spain.
authors.forename: Cristina
authors.initials: C
authors.lastname: López-Rodríguez
authors.affiliation: Department of Experimental and Health Sciences, Universitat Pompeu Fabra, Barcelona, Spain.
authors.forename: Jose
authors.identifier: 0000-0001-9279-9523
authors.initials: J
authors.lastname: Aramburu
mesh_terms: D000818:Animals; D003092:Colitis / Q000276:immunology / Q000473:pathology; D016264:Dextran Sulfate; D005786:Gene Expression Regulation; D006955:Hypernatremia / Q000235:genetics; D007371:Interferon-gamma / Q000378:metabolism*; D007376:Interleukin-2 / Q000378:metabolism; D008213:Lymphocyte Activation; D051379:Mice; D050778:NFATC Transcription Factors / Q000378:metabolism*; D009997:Osmotic Pressure; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory; D058504:Th17 Cells / Q000378:metabolism*
chemical_list: D007376:Interleukin-2; D050778:NFATC Transcription Factors; D012333:RNA, Messenger; D007371:Interferon-gamma; D016264:Dextran Sulfate