NFAT proteins: key regulators of T-cell development and function

Macian, Fernando

doi:10.1038/nri1632

Cited by 1,347 publications

(1,353 citation statements)

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“…Indeed, Dectin-1 induces the expression of genes such as IL-2 and COX-2 in an NFAT-dependent fashion [28,29]. The activation of NFAT is tightly regulated by calcium.…”

Section: Dectin-1 Requires Plcc2 For Ap-1 Nf-jb and Nfat Activationmentioning

confidence: 99%

Requirement of phospholipase C‐γ2 (PLCγ2) for Dectin‐1‐induced antigen presentation and induction of T_H1/T_H17 polarization

et al. 2009

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DC recognize microbial components through an array of receptors known as PRR. PRR initiate intracellular signals, which engender DC with the capacity to stimulate T-cell responses. Dectin-1 is a PRR that recognizes b-glucan, a major constituent of many fungi's outer cell wall. Here we show that Dectin-1 activates DC through phospholipase (PLC)c2 signaling. PLCc2-deficient DC were unable to expand antigen-specific T cells and induce T H 1 and T H 17 differentiation in response to b-glucan. Mechanistically, PLCc2-deficiency impaired the capacity of DC to secrete polarizing cytokines following exposure to b-glucan. Dectin-1 required PLCc2 to activate MAPK, AP-1 and NF-jB, which induce cytokine gene expression. Moreover, PLCc2 controlled Dectin-1-mediated NFAT activation and induction of NFAT-dependent genes such as IL-2, cyclooxigenase-2 and Egr transcription factors. We conclude that PLCc2 is a crucial signaling mediator that modifies DC gene expression program to activate DC responses to b-glucan-containing pathogens.Key words: DC . Dectin-1 . PLCg . Signaling Supporting Information available online Introduction DC play a key role in gathering information from the surrounding environment and initiating appropriate immune responses when needed [1,2]. Because they bridge innate and adaptive immunity, DC are equipped with a multitude of intracellular and cell surface receptors that sense microbial components and trigger host responses to invading pathogens. These receptors, collectively known as PRR, include TLR [3], C-type lectins such as Dectin-1 [4], scavenger receptors [5], the nucleotide-binding oligomerization domain (NOD) proteins NOD1 and NOD2, the NOD-like receptors and the RIG-like receptors [6].Dectin-1 recognizes b-glucan, a major constituent of many fungi's outer cell wall [4,7] and triggers intracellular signals through a cytoplasmic tyrosine motif resembling the ITAM. Upon ligand binding, this motif is phosphorylated by src family kinases [8] and recruits the tyrosine kinase Syk [9], which initiates a signaling cascade leading to NF-kB [10], NFAT [11] and MAPK [12] activation. Along with Bcl-10 and MALT1, CARD9 is a crucial mediator in the ITAM-signaling pathway that links recognition of b-glucan by Dectin-1 to NF-kB and MAPK activation [13,14]. Overall, the Syk-CARD9 pathway is essential for [20,21]. Syk, together with the tyrosine kinases BTK and Src, activate PLCg through tyrosine phosphorylation [22]. Another downstream ITAM mediator, PI-3K, activates PLCg by generating phosphatidylinositol 3,4,5 trisphosphate, which binds the pleckstrin homology domain of PLCg, promoting PLCg recruitment to the cell membrane. Thus, the ability of Dectin-1 to initiate an ITAM-Syk-signaling pathway [9] provides a rationale for studying the role of PLCg in Dectin-1-mediated antimicrobial responses in DC.PLCg includes two isoforms, PLCg1 and PLCg2, which hydrolyze membrane phosphatidylinositol 4,5-biphosphate into inositol 1,4,5-trisphosphate and diacylglicerol (DAG) [20]. Inositol 1,4,5-trisphosphate triggers the ...

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“…Indeed, Dectin-1 induces the expression of genes such as IL-2 and COX-2 in an NFAT-dependent fashion [28,29]. The activation of NFAT is tightly regulated by calcium.…”

Section: Dectin-1 Requires Plcc2 For Ap-1 Nf-jb and Nfat Activationmentioning

confidence: 99%

Requirement of phospholipase C‐γ2 (PLCγ2) for Dectin‐1‐induced antigen presentation and induction of T_H1/T_H17 polarization

et al. 2009

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“…T-cell receptor (TCR) engagement in naïve T cells initiates changes in gene expression that are essential for the generation of effector T cells. They require the activation of transcription factors, primarily NF-kB and NFAT [2,3]. TCR/CD28-induced NF-kB activation characteristically elicits the expression of both IL-2 and IL-2 receptor a chain together with the antiapoptotic molecule Bcl-x L [2].…”

Section: Introductionmentioning

confidence: 99%

Critical role of the calpain/calpastatin balance in acute allograft rejection

et al. 2010

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Rejection of solid organ allograft involves alloreactive T-cell expansion. The importance of NF-jB and NFAT in this process is underscored by the therapeutic efficacy of immunosuppressive agents, which target the two transcription factors. Since calpains, calciumactivated proteases, are involved in the activation of NF-jB and NFAT, we investigated the role of calpains in allograft rejection. In human transplant kidneys undergoing acute or chronic rejection, we show an increased expression of CAPN 1 gene encoding l-calpain, associated with a marked expression of l-calpain, mainly in infiltrating T cells. To address the role of calpain in rejection, we used a skin transplant model in transgenic mice expressing high levels of calpastatin, a calpain-specific inhibitor. We show that calpain inhibition extended skin allograft survival, from 11 to 20 days. This delay was associated with a limitation in allograft infiltration by T cells. In vitro, calpain inhibition by calpastatin transgene expression limited dramatically T-cell migration but, unexpectedly, increased slightly T-cell proliferation. Amplification of IL-2 signaling via the stabilization of IL-2R common c-chain provided an explanation for the proliferation response. This is the first study establishing that calpain inhibition delays allograft rejection by slowing down T-cell migration rather than proliferation.Key words: Allograft . Calpain . Calpastatin . T cells IntroductionSolid organ transplantation represents an important means of treating end stage organ failure. However, this strategy is limited by the immune response mounted by the recipient against donor tissue. Acute allograft rejection involves T cells of the adaptive immune system in addition to cells of the innate immune system [1]. T-cell receptor (TCR) engagement in naïve T cells initiates changes in gene expression that are essential for the generation of effector T cells. They require the activation of transcription factors, primarily NF-kB and NFAT [2,3]. TCR/CD28-induced NF-kB activation characteristically elicits the expression of both IL-2 and IL-2 receptor a chain together with the antiapoptotic molecule Bcl-x L [2]. NFAT, which is activated by the calmodulin-dependent phosphatase calcineurin, is also required for the expression of the IL-2 gene through its interaction with proteins of the AP1 family of transcription factors [3]. Given the importance of these two pathways in the generation Ã These authors contributed equally to this work. Eur. J. Immunol. 2011. 41: 473-484 DOI 10.1002 Leukocyte signaling 473 of effector T cells, a number of different pharmacological inhibitors of NF-kB and/or calcineurin/NFAT are currently used as immunosuppressive agents in transplantation, including steroids, cyclosporin A and tacrolimus (FK-506) [4]. Calpains are calcium-activated neutral cysteine proteases [5]. Two major isoforms, calpain m (or I) and calpain m (or II), which require micromolar and millimolar Ca 21 concentrations for activity, respectively, are ubiquitously expressed, whereas the ...

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“…Activated NFAT migrates into the nucleus, where it binds to and activates the promoters of several genes, including IL-2 (Ca 2+ -NFAT pathway) ( Figure 5). [80][81][82] Although a total of three isoenzymes of ITPK proteins (ITPKA, ITPKB, and ITPKC) are known to date, the importance of ITPKC in the immune system has not been identified. We investigated mRNA expression of ITPKC in a variety of tissues and revealed that ITPKC was strongly induced in stimulated peripheral blood mononuclear cells (PBMCs).…”

Section: Identification Of Itpkc As a Susceptibility Gene For Kdmentioning

confidence: 99%

Susceptibility genes for Kawasaki disease: toward implementation of personalized medicine

Hata

Onouchi

2009

J Hum Genet

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Kawasaki disease (KD) is an acute systemic vasculitis syndrome, which primarily affects in children under the age of 5 years. In 20-25% of cases, if untreated, coronary artery lesions develop, making KD the leading cause of acquired heart disease in children in both Japan and the United States. Since 1970, 19 nationwide surveys of KD in Japan have been conducted every 2 years and the data are stored in a database. Even though the etiology of KD remains unknown, despite enthusiastic research spanning more than 40 years, we have learnt a great deal about KD from this enormous database. These 19 epidemiologic studies indicate a strong genetic influence on the disease susceptibility, prompting us and other researchers to identify the responsible genes for KD by applying either the candidate gene approach or the genome-wide approach. We have employed a genome-wide linkage study using affected sibling pair data of KD in Japan and have identified several susceptibility loci. Further analysis focusing on a region of chromosome 19, where one of the linked loci was detected, identified a predisposing gene, which codes inositol 1,4,5-trisphosphate 3-kinase C (ITPKC). In this review, we summarize the cumulative knowledge regarding KD, and then outline our hypothesis of the role ITPKC plays in KD susceptibility and our trial that aims toward the implementation of personalized medicine for KD.

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NFAT proteins: key regulators of T-cell development and function

Cited by 1,347 publications

References 132 publications

Requirement of phospholipase C‐γ2 (PLCγ2) for Dectin‐1‐induced antigen presentation and induction of T_H1/T_H17 polarization

Requirement of phospholipase C‐γ2 (PLCγ2) for Dectin‐1‐induced antigen presentation and induction of T_H1/T_H17 polarization

Critical role of the calpain/calpastatin balance in acute allograft rejection

Susceptibility genes for Kawasaki disease: toward implementation of personalized medicine

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NFAT proteins: key regulators of T-cell development and function

Cited by 1,347 publications

References 132 publications

Requirement of phospholipase C‐γ2 (PLCγ2) for Dectin‐1‐induced antigen presentation and induction of TH1/TH17 polarization

Requirement of phospholipase C‐γ2 (PLCγ2) for Dectin‐1‐induced antigen presentation and induction of TH1/TH17 polarization

Critical role of the calpain/calpastatin balance in acute allograft rejection

Susceptibility genes for Kawasaki disease: toward implementation of personalized medicine

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Requirement of phospholipase C‐γ2 (PLCγ2) for Dectin‐1‐induced antigen presentation and induction of T_H1/T_H17 polarization

Requirement of phospholipase C‐γ2 (PLCγ2) for Dectin‐1‐induced antigen presentation and induction of T_H1/T_H17 polarization