Dependence on nuclear factor of activated T-cells (NFAT) levels discriminates conventional T cells from Foxp3 ⁺ regulatory T cells

Abstract

Several lines of evidence suggest nuclear factor of activated T-cells (NFAT) to control regulatory T cells: thymus-derived naturally occurring regulatory T cells (nTreg) depend on calcium signals, the Foxp3 gene harbors several NFAT binding sites, and the Foxp3 (Fork head box P3) protein interacts with NFAT. Therefore, we investigated the impact of NFAT on Foxp3 expression. Indeed, the generation of peripherally induced Treg (iTreg) by TGF-β was highly dependent on NFAT expression because the ability of CD4 + T cells to differentiate into iTreg diminished markedly with the number of NFAT family members missing. It can be concluded that the expression of Foxp3 in TGF-β-induced iTreg depends on the threshold value of NFAT rather than on an individual member present. This is specific for iTreg development, because frequency of nTreg remained unaltered in mice lacking NFAT1, NFAT2, or NFAT4 alone or in combination. Different from expectation, however, the function of both nTreg and iTreg was independent on robust NFAT levels, reflected by less nuclear NFAT in nTreg and iTreg. Accordingly, absence of one or two NFAT members did not alter suppressor activity in vitro or during colitis and transplantation in vivo. This scenario emphasizes an inhibition of high NFAT activity as treatment for autoimmune diseases and in transplantation, selectively targeting the proinflammatory conventional T cells, while keeping Treg functional.gene regulation | tolerance | autoimmunity

STIM1 controls T cell–mediated immune regulation and inflammation in chronic infection

“…This is in line with recent studies showing that members of the Ca 2+ -dependent NFAT transcription factor family regulate FOXP3 expression in iTregs (68,69). NFAT binds, together with SMAD2/3, directly to the conserved noncoding sequence 1 in the Foxp3 locus and regulates FOXP3 expression in response to TCR stimulation and TGF-β (68)(69)(70). In addition to Foxp3, expression of other genes associated with iTregs was significantly deregulated in STIM1-deficient T cells.…”

“…Similar observations were made in NFAT2-deficient CD4 + T cells, which fail to efficiently differentiate into FOXP3 + iTregs, while the remaining iTregs were functional (68). Together, our data indicate that STIM1-mediated Ca 2+ signaling is essential for the conversion of naive CD4 + T cells into iTregs, but that it is largely dispensable for their stability and suppressive functions.…”

“…Statistical significance was calculated by Student's t test. *P < 0.05; **P < 0.01; ***P < 0.001. jci.org Volume 125 Number 6 June 2015 mice are unable to differentiate into iTregs, whereas nTreg development and function are normal (68,74). These findings suggest that the lymphoproliferative phenotype observed in Stim1 CD4 mice chronically infected with Mtb is caused by impaired iTreg differentiation rather than defective nTreg development (38,75,76).…”

IL-2 therapy restores regulatory T-cell dysfunction induced by calcineurin inhibitors

“…Second, analysis of NFAT translocation demonstrated that, compared with Teffs, Tregs displayed an increased nuclear localization of NFAT in the presence of tacrolimus. These data differ from two previous publications reporting reduced effects of CNIs on Tregs (28,29). Vaeth et al (29) failed to detect NFAT in the nucleus of Tregs and concluded that their function …”

Inhibition of FOXP3/NFAT Interaction Enhances T Cell Function after TCR Stimulation

“…In particular, it has been demonstrated that the generation of peripherally induced Tregs by TGF-b is highly dependent on NFAT expression (48). NFAT proteins interact with Fos-Jun (AP-1) transcription factors to form cooperative NFAT/AP-1 complexes that are critical for the induction of cytokine genes and other activation-associated genes.…”