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 kappa B 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 ROR gamma t 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 gamma (IFN gamma) 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 IFN gamma in draining lymph nodes and colon. These results show that NFAT5 can modulate different T-cell responses depending on stress conditions and stimulatory context.