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

Alberdi Ibarzabal, Maria, 1986-; Iglesias, Marcos; Tejedor Vaquero, Sonia, 1988-; Merino, Ramón; López Rodríguez, M. Cristina; Aramburu, José (Aramburu Beltrán)

doi:http://dx.doi.org/10.1038/icb.2016.69

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

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Alberdi Ibarzabal M, Iglesias M, Tejedor Vaquero S, Merino R, López Rodríguez MC, Aramburu J. Context-dependent regulation of Th17-associated genes and IFNγ expression by the transcription factor NFAT5. Immunology and Cell Biology. 2017;95:56-67. DOI: 10.1038/icb.2016.69

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.