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, 270 (1-2), 13-21

FTY720 Impairs CD8 T-cell Function Independently of the sphingosine-1-phosphate Pathway

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FTY720 Impairs CD8 T-cell Function Independently of the sphingosine-1-phosphate Pathway

Achilles Ntranos et al. J Neuroimmunol.

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.

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

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