FTY720 impairs CD8 T-cell function independently of the sphingosine-1-phosphate pathway

Ntranos, Achilles; Hall, O.; Robinson, Dionne P.; Grishkan, Inna V.; Schott, Jason T.; Tosi, Dominique M.; Klein, Sabra L.; Calabresi, Peter A.; Gocke, Anne R.

doi:10.1016/j.jneuroim.2014.03.007

Cited by 44 publications

(54 citation statements)

References 36 publications

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“…15 In addition to immune cells, fingolimod has been shown to interact directly with CNS-specific cell types, such as astrocytes. 16 In summary, the effects of fingolimod are manifold and extend well beyond lymphocyte trafficking.…”

Section: Resultsmentioning

confidence: 99%

Successful treatment with fingolimod of graft-versus-host disease of the central nervous system

Gauthier¹,

Vermersch

Chauvet³

et al. 2018

Blood Advances

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Section: Resultsmentioning

confidence: 99%

Successful treatment with fingolimod of graft-versus-host disease of the central nervous system

Gauthier¹,

Vermersch

Chauvet³

et al. 2018

Blood Advances

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“…While preparing this manuscript Ntranos et al. showed that FTY720 also inhibited the αCD3/αCD28‐induced production of IFN‐ γ and cytotoxicity of CD8 + T cells in vitro and in vivo. These results indicate that the effect of FTY720 is conserved for IFN‐ γ and not dependent on the stimulus.…”

Section: Discussionmentioning

confidence: 99%

Fingolimod targeting protein phosphatase 2A differently affects IL‐33 induced IL‐2 and IFN‐γ production in CD8⁺ lymphocytes

et al. 2016

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Multiple sclerosis patients are treated with fingolimod (FTY720), a prodrug that acts as an immune modulator. FTY720 is first phosphorylated to FTY720-P and then internalizes sphingosine-1-phosphate receptors, preventing lymphocyte sequestration. IL-33 is released from necrotic endothelial cells and contributes to MS severity by coactivating T cells. Herein we analyzed the influence of FTY720, FTY720-P, and S1P on IL-33 induced formation of IL-2 and IFN-γ, by using IL-33 receptor overexpressing EL4 cells, primary CD8 + T cells, and splenocytes. EL4-ST2 cells released IL-2 after IL-33 stimulation that was inhibited dose-dependently by FTY720-P but not FTY720. In this system, S1P increased IL-2, and accordingly, inhibition of S1P producing sphingosine kinases diminished IL-2 release. In primary CD8 + T cells and splenocytes IL-33/IL-12 stimulation induced IFN-γ, which was prevented by FTY720 but not FTY720-P, independently from intracellular phosphorylation. The inhibition of IFN-γ by nonphosphorylated FTY720 was mediated via the SET/protein phosphatase 2A (PP2A) pathway, since a SET peptide antagonist also prevented IFN-γ formation and the inhibition of IFN-γ by FTY720 was reversible by a PP2A inhibitor. While our findings directly improve the understanding of FTY720 therapy in MS, they could also contribute to side effects of FTY720 treatment, like progressive multifocal leukoencephalopathy, caused by an insufficient immune response to a viral infection.Keywords: CD8 + T cells r Fingolimod (FTY720) r IL-33 r Multiple sclerosis r Protein phosphatase 2a (PP2A)Additional supporting information may be found in the online version of this article at the publisher's web-site IntroductionMultiple sclerosis is an autoimmune disorder, characterized by the destruction of the myelin sheath by autoreactive immune cells, leading to astrogliosis, demyelination, and increasing disability. Most patients are diagnosed between 20 and 40 years, Correspondence: Dr. Heinfried H. Radeke e-mail: radeke@em.uni-frankfurt.de with a 2:1 female to male ratio [1]. Fingolimod (2-amino-2-[2-(4-octylphenyl)ethyl]-propane-1,3-diol; FTY720) is an immunemodulating prodrug derived from the natural compound myriocin and was approved in 2010 as the first oral treatment for relapsing-remitting MS. Its phosphorylated derivative is an analog of the bioactive sphingolipid sphingosine-1-phosphate (S1P), which is involved in cellular processes such as cell cycle, apoptosis, or immune modulatory processes such as migration or the regulation of cytokine expression [2,3]. Extracellular lipophilic C 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu 942Florian Ottenlinger et al. Eur. J. Immunol. 2016. 46: 941-951 FTY720 or sphingosine easily passes the membrane of immune cells to the intracellular space. Here, sphingosine is phosphorylated by the sphingosine kinases (SphKs) SphK1 and SphK2 to S1P, whereas FTY720 is phosphorylated by SphK2 to FTY720-phosphate (FTY720-P) [4]. Once phosphorylated, the amphiphilic nature of FTY720-P or S1P prev...

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“…In EAE several additional effects on the immune system have been shown: Fingolimod changes CD8+ effector T cell function and inhibits their cytotoxic function by inhibition of cytosolic PLA 2 and the reduction of IFNγ and Granzyme B expression. Interestingly, this effect appears to be independent of S1P receptor modulation as fingolimod phosphate did not elicit these effects (Ntranos et al, 2014). In some EAE-studies, the effect of fingolimod on CNS physiology was analyzed.…”

Section: Fingolimod In Experimental Models Of Multiple Sclerosismentioning

confidence: 99%

Fingolimod for the treatment of neurological diseasesâ€”state of play and future perspectives

Brunkhorst

Vutukuri

Pfeilschifter

2014

Front. Cell. Neurosci.

126

116

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Sphingolipids are a fascinating class of signaling molecules derived from the membrane lipid sphingomyelin. They show abundant expression in the brain. Complex sphingolipids such as glycosphingolipids (gangliosides and cerebrosides) regulate vesicular transport and lysosomal degradation and their dysregulation can lead to storage diseases with a neurological phenotype. More recently, simple sphingolipids such ceramide, sphingosine and sphingosine 1-phosphate (S1P) were discovered to signal in response to many extracellular stimuli. Forming an intricate signaling network, the balance of these readily interchangeable mediators is decisive for cell fate under stressful conditions. The immunomodulator fingolimod is the prodrug of an S1P receptor agonist. Following receptor activation, the drug leads to downregulation of the S1P1 receptor inducing functional antagonism. As the first drug to modulate the sphingolipid signaling pathway, it was marketed in 2010 for the treatment of multiple sclerosis (MS). At that time, immunomodulation was widely accepted as the key mechanism of fingolimod’s efficacy in MS. But given the excellent passage of this lipophilic compound into the brain and its massive brain accumulation as well as the abundant expression of S1P receptors on brain cells, it is conceivable that fingolimod also affects brain cells directly. Indeed, a seminal study showed that the protective effect of fingolimod in experimental autoimmune encephalitis (EAE), a murine MS model, is lost in mice lacking the S1P1 receptor on astrocytes, arguing for a specific role of astrocytic S1P signaling in MS. In this review, we discuss the role of sphingolipid mediators and their metabolizing enzymes in neurologic diseases and putative therapeutic strategies arising thereof.

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FTY720 impairs CD8 T-cell function independently of the sphingosine-1-phosphate pathway

Cited by 44 publications

References 36 publications

Successful treatment with fingolimod of graft-versus-host disease of the central nervous system

Successful treatment with fingolimod of graft-versus-host disease of the central nervous system

Fingolimod targeting protein phosphatase 2A differently affects IL‐33 induced IL‐2 and IFN‐γ production in CD8⁺ lymphocytes

Fingolimod for the treatment of neurological diseasesâ€”state of play and future perspectives

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FTY720 impairs CD8 T-cell function independently of the sphingosine-1-phosphate pathway

Cited by 44 publications

References 36 publications

Successful treatment with fingolimod of graft-versus-host disease of the central nervous system

Successful treatment with fingolimod of graft-versus-host disease of the central nervous system

Fingolimod targeting protein phosphatase 2A differently affects IL‐33 induced IL‐2 and IFN‐γ production in CD8+ lymphocytes

Fingolimod for the treatment of neurological diseasesâ€”state of play and future perspectives

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Fingolimod targeting protein phosphatase 2A differently affects IL‐33 induced IL‐2 and IFN‐γ production in CD8⁺ lymphocytes