Fingolimod Increases CD39-Expressing Regulatory T Cells in Multiple Sclerosis Patients

Abstract

BackgroundMultiple sclerosis (MS) likely results from an imbalance between regulatory and inflammatory immune processes. CD39 is an ectoenzyme that cleaves ATP to AMP and has been suggested as a novel regulatory T cells (Treg) marker. As ATP has numerous proinflammatory effects, its degradation by CD39 has anti-inflammatory influence. The purpose of this study was to explore regulatory and inflammatory mechanisms activated in fingolimod treated MS patients.Methods and FindingsPeripheral blood mononuclear cells (PBMCs) were isolated from relapsing-remitting MS patients before starting fingolimod and three months after therapy start. mRNA expression was assessed in ex vivo PBMCs. The proportions of CD8, B cells, CD4 and CD39-expressing cells were analysed by flow cytometry. Treg proportion was quantified by flow cytometry and methylation-specific qPCR. Fingolimod treatment increased mRNA levels of CD39, AHR and CYP1B1 but decreased mRNA expression of IL-17, IL-22 and FOXP3 mRNA in PBMCs. B cells, CD4+ cells and Treg proportions were significantly reduced by this treatment, but remaining CD4+ T cells were enriched in FOXP3+ cells and in CD39-expressing Tregs.ConclusionsIn addition to the decrease in circulating CD4+ T cells and CD19+ B cells, our findings highlight additional immunoregulatory mechanisms induced by fingolimod.

The influence of gut-derived CD39 regulatory T cells in CNS demyelinating disease

“…Recent studies show that approved MS therapeutics, such as fingolimod, increases CD39-expressing regulatory T cells in MS patients, as measured by mRNA expression levels of CD39 and by flow cytometry. 92 These striking observations has been supported by recent studies in our laboratory where it was observed that treatment with alemtuzumab, a humanized anti-CD52 monoclonal antibody (mAb), reduced the frequencies of circulating CD4 + T cells; however, the remaining population had an enhanced expression of Foxp3 and CD39 (Mielcarz, et al presented at ECTRIMS 2013 93 ). Similar findings have been observed in EAE mice treated with a murine anti-CD52 mAb (Pant et.…”

A commensal symbiotic factor derived fromBacteroides fragilispromotes human CD39+Foxp3+T cells and Tregfunction

“…Interestingly, 3 months of treatment with sphingosine-1-phosphate receptor antagonist FTY720 similarly enhanced CD39 GMFI as well as frequencies of CD39 C Foxp3 C T regs in patients, suggesting the therapeutic value of these cells. 39 Further support for the importance of these cells in MS stems from the positive correlation of increased CD39 C T reg frequency and disease remission. 40 Finally, these results parallel our findings in mice showing enhanced CD39 C Foxp3 C T regs in the CNS of PSA treated animals during EAE.…”

IL-17–Producing Vγ4+ γδ T Cells Require Sphingosine 1-Phosphate Receptor 1 for Their Egress from the Lymph Nodes under Homeostatic and Inflammatory Conditions

“…Vg9Vd2 T cells produced large amounts of IL-17 in the presence of IL-1b, IL-23, IL-6, and TGF-b (46). Moreover, it has been reported that the frequency of gd T cells is significantly increased in the PBL from MS patients, and FTY720 administration resulted in a marked reduction of IL-17 production by PBL stimulated with anti-CD3 and anti-CD28 mAbs in vitro (11,22,47). Based on these findings, it is highly probable that inhibition of S1P1-dependent egress of pathogenic IL-17-producing gd T cells partly contributes to the therapeutic effects of FTY720 on mouse EAE and relapsing MS.…”