NFATc1 deficiency in T cells protects mice from experimental autoimmune encephalomyelitis

Abstract

NFATc1 is a member of the nuclear factor of activated T cells (NFAT) family of transcription factors. NFAT is activated upon T-cell receptor activation followed by intracytoplasmatic Keywords: CD4+ T cells r EAE r NFAT r RORγT r Th17Additional supporting information may be found in the online version of this article at the publisher's web-site IntroductionNuclear factor of activated T cells (NFAT) was originally described as a transcription factor inducing the expression of interleukin 2 (IL-2) [1]. The NFAT family of transcription factors consists of five members, named NFAT1-5, and the main forms expressed in T cells are NFATc1 and NFATc2 [2]. NFATc2 is constitutively expressed in T cells [3], whereas NFATc1 is activated upon T-cell receptor stimulation [4]. NFATc1 is the only NFAT protein Correspondence: Prof. Susetta Finotto e-mail: susetta.finotto@uk-erlangen.de family member which acts in a positive autoregulatory loop [5] and thereby augments NFATc1 expression. NFAT proteins reside phosphorylated in the cytoplasm. Upon T-cell receptor activation the phospholipase C signaling pathway is activated, which leads to an induced influx of calcium into the cell. Intracytoplasmatic calcium signaling activates calmodulin, a calcium sensor protein that activates the phosphatase calcineurin. These phosphatase dephosphorylates NFAT proteins, so that they can shuttle into the nucleus where they act as transcription factors on the promoter of target * These authors contributed equally to this work. www.eji-journal.euThis is an open access article under the terms of the Creative Commons Attribution-NonCommercialNoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.Eur. J. Immunol. 2015Immunol. . 45: 1426Immunol. -1440 Immunomodulation 1427 genes such as . Previous studies showed that NFAT proteins play regulatory roles during T-cell differentiation and effector functions. NFATc2 deficiency in T cells diminished Th1 differentiation and induced IL-4 production [7,8]. NFATc2 was also shown to contribute to IL-21 expression and to limit the immunosuppressive function of CD4 + CD25 + Foxp3 + GITR + T regulatory (Treg) cells [8,9]. The role of NFATc1 in T-cell differentiation processes is not fully understood, partially because NFATc1 total knockout mice die at the embryonic stage [10]. Previous analysis on Th1-and Th2-skewed T cells isolated from NFATc1−/− /Rag1 −/− chimeric mice revealed an involvement of NFATc1 in the induction of the Th2-cytokines IL-4 and IL-6, whereas it had no effect on interferon gamma (IFN-γ) and IL-2 expression in Th1 cells [11,12]. Other studies showed that NFATc1 induces IL-4 expression. In Th17 cells, NFAT transcription factors have been shown to be involved in the gene expression of RORγT (where ROR is RARrelated orphan receptor), . This has been shown mostly for other NFAT transcription factor family members than NFATc1. EAE is the murine model for the early in...

NFAT2 Regulates Generation of Innate-Like CD8+ T Lymphocytes and CD8+ T Lymphocytes Responses

“…Previous studies using NFAT2 −/− /Rag-1 −/− chimeric mice likewise reported impaired proliferation of NFAT2-deficient T cells ( 38 ) but independently of autocrine IL-2 secretion. In the EAE model, NFAT2 deficiency reduced the proliferation capacity of MOG-specific T cells in IL-2-dependent and -independent manners ( 41 ). In our model, CD8 + T cells produced less IL-2 under suboptimal TCR stimulation, and NFAT2 deficiency reduced proliferation in IL-2-dependent manner.…”

“…NFAT2 binding sites were found within the Il17a promoter ( 39 ) and the Il10 promoter ( 40 ). Recently, NFAT2 has been shown as a positive regulator of RORγT and Th17 cytokines during TGF-β-mediated Th17-cell differentiation ( 41 ). NFAT2-deficient TGF-β-induced iTreg cells showed a slight reduction of CD25 and Foxp3 expression as compared to WT cells ( 42 ), indicating no essential role for NFAT2 in iTreg cell development.…”

Rhinovirus inhibits IL-17A and the downstream immune responses in allergic asthma

“…It is produced by T helper type 17 (Th17) cells and it is also associated with autoimmune diseases. 12 IL-17A was found upregulated in moderate to severe asthma where it contributes, e.g., to accumulation of neutrophils in the airways. 13 Schnyder-Candrian et al 14 showed that exogenous rmIL-17A during allergen challenge decreased airway hyperresponsiveness (AHR).…”

Cutting Edge: NFAT Transcription Factors Promote the Generation of Follicular Helper T Cells in Response to Acute Viral Infection

“…NFAT1, NFAT2 and NFAT4 are expressed in cells of the immune system and have important roles in T cell development and function (3). While NFAT family members make similar contacts with DNA (4), they show distinct expression patterns and functions, as judged by the non-overlapping phenotypes of mice deficient in individual NFAT family members ((5, 6) and reviewed in (7)).…”