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

BACKGROUND: Multiple 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 FINDINGS: Peripheral 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. CONCLUSIONS: In addition to the decrease in circulating CD4(+) T cells and CD19(+) B cells, our findings highlight additional immunoregulatory mechanisms induced by fingolimod.