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.

Roquin targets mRNAs in a 3′-UTR-specific manner by different modes of regulation

“…Among the identified Roquin targets that are regulated only by mRNA stability or additionally by translational inhibition are Sgk1 and Nfat5 , respectively, two signaling molecules activated by osmotic stress and that have been implicated in Th17 differentiation 36 – 39 . Deregulation of these factors, in addition to the known targets Nfkbiz and Nfkbid , Irf4 and cRel , may contribute to the strong Th17 differentiation phenotype 9 , 40 – 46 that has been observed in Roquin-deficient CD4 + T cells 6 , 7 .…”

NFAT5 Has a Job in the Brain

“…NFAT5 was necessary for naïve Th cell differentiation to Th17 cells and the polarization and activation of Th17 cells [46-48]. The activation of Th17 cells and pro-inflammatory cytokine secretion were aggravated in an experimental autoimmune encephalomyelitis model and high-salt diet by activating the NFAT5 pathway via p38/MAPK [46].…”

“…The activation of Th17 cells and pro-inflammatory cytokine secretion were aggravated in an experimental autoimmune encephalomyelitis model and high-salt diet by activating the NFAT5 pathway via p38/MAPK [46]. Moreover, when T cells were exposed to hypernatremia induced by a high-salt diet, interleukin (IL)-2, CD24, and Th17 cell-associated genes, such as retinoic acid receptor-related orphan nuclear receptor gamma (RORγ) which was specifically expressed in immune cells and IL-23 receptor (IL-23R), were unregulated by NFAT5 [48, 49]. NFAT5 also promoted the activation of Tregs by upregulating the expression of IL-2.…”

NFAT5-Regulated Macrophage Polarization Supports the Proinflammatory Function of Macrophages and T Lymphocytes

“…Mouse models deficient for the transcription factor NFAT5 have become instrumental for the identification of specific roles of this factor in different immune cells. In this regard, although its function in B and T lymphocytes has been mainly studied in hypertonicity-induced transcription responses (30)(31)(32), in innate immune cells such as macrophages NFAT5 has been shown to be required for TLR-induced responses to pathogens (33), a role that NFAT5 performs in isotonic conditions (33) but that can be enhanced under hypernatremia (34). As we had previously found that many of the TLR-induced NFAT5-regulated genes, such as inducible NO synthase (iNOS) or TNF-a, have a central role in inflammatory responses (33), we were interested in understanding the contribution of NFAT5 to the balance between classically or alternatively activated macrophage functions.…”