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J Neuroimmunol. 2014 May 15;270(1-2):13-21. doi: 10.1016/j.jneuroim.2014.03.007. Epub 2014 Mar 11.

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

Author information

  • 1Department of Neurology, Johns Hopkins University School of Medicine, 600 N. Wolfe St., Baltimore, MD 21287, USA.
  • 2W. Harry Feinstone Department of Molecular Microbiology and Immunology, The Johns Hopkins Bloomberg School of Public Health, 615 N. Wolfe St., Baltimore, MD 21205, USA.
  • 3Department of Neurology, Johns Hopkins University School of Medicine, 600 N. Wolfe St., Baltimore, MD 21287, USA. Electronic address: pcalabr1@jhmi.edu.
  • 4Department of Neurology, Johns Hopkins University School of Medicine, 600 N. Wolfe St., Baltimore, MD 21287, USA. Electronic address: agocke4@jhu.edu.

Abstract

Fingolimod (FTY720) is a multiple sclerosis (MS) therapeutic that upon phosphorylation causes the internalization of sphingosine-1-phosphate receptors (S1PR) and traps CCR7+ T-cells in lymph nodes but relatively spares CCR7-effector T-cells. Nonetheless, FTY720-treated patients are more susceptible to viral infections, indicating a CD8 T-cell defect. Thus, the effects of FTY720 on CD8 T-cells were investigated. To this end, we utilized experimental autoimmune encephalomyelitis (EAE) and a murine influenza model. CD8 T-cell trafficking, IFNγ and Granzyme B (GrB) production were assessed by flow cytometry. CD8 T-cell cytotoxic function was assessed in vitro by an LDH release assay. FTY720 not only ameliorated EAE by sequestering T-cells, but also reduced IFNγ and Granzyme B (GrB) in splenic CD8 T-cells. Murine influenza infection was exacerbated and mortality was increased, as FTY720 inhibited CD8 T-cell GrB production and lung infiltration. Remarkably, only the unphosphorylated compound was able to reduce IFNγ and GrB levels in CD8 T-cells and inhibits their cytotoxic function in vitro. The phosphorylated moiety had no effect in vitro, indicating that CD8 T-cell suppression by FTY720 is independent of S1PR modulation. The addition of arachidonic acid rescued CD8 T-cell function, suggesting that this effect may be mediated via inhibition of cytosolic phospholipase A2. Herein, we demonstrate that FTY720 suppresses CD8 T-cells independently of its trafficking effects and S1PR modulation. This provides a novel explanation not only for the increased rate of viral infections in FTY720-treated patients, but also for its efficacy in MS, as CD8 T-cells have emerged as crucial mediators of MS pathogenesis.

Copyright © 2014 Elsevier B.V. All rights reserved.

KEYWORDS:

Autoimmunity; CD8+ T cells; Experimental autoimmune encephalomyelitis (EAE); Fingolimod (FTY720); Murine influenza; Viral infection

PMID:
24680062
[PubMed - indexed for MEDLINE]
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