Abstract: Stress-activated transcription factors influence T-cell function in different physiopathologic contexts. NFAT5, a relative of nuclear
factor ?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?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 ? (IFN?) 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? in draining lymph nodes and colon. These results show that NFAT5 can
modulate different T-cell responses depending on stress conditions and stimulatory context
