Peripheral CD39-expressing T regulatory cells are increased and associated with relapsing-remitting multiple sclerosis in relapsing patients

Nuria Álvarez-Sánchez,María Díaz-Sánchez,Antonio Carrillo-Vico,Patricia Judith Lardone,Ivan Cruz-Chamorro,Juan Miguel Guerrero

doi:10.1038/s41598-019-38897-w

Abstract

CD39, an ectonucleotidase that hydrolyses pro-inflammatory ATP, is a marker of highly active and suppressive T regulatory cells (Tregs). Although CD39 has a role in Treg suppression and might be important in the control of neuroinflammation in relapsing-remitting multiple sclerosis (RR-MS), to date, there are contradictory reports concerning the Tregs expression of CD39 in RR-MS patients. Thus, our objectives were to assess the activity and expression of CD39, especially in Tregs from peripheral blood mononuclear cells (PBMCs) of relapsing RR-MS patients compared with control subjects and to evaluate the association of CD39+ Tregs with disability and the odds of RR-MS. The activity and expression of CD39 and the CD39+ Treg frequency were measured in PBMCs from 55 relapsing RR-MS patients (19 untreated and 36 receiving immunomodulatory treatment) and 55 age- and sex-paired controls. Moreover, the association between CD39+ Tregs and RR-MS was assessed by multivariate logistic regression. CD39 activity and the frequency of CD39-expressing Tregs were elevated in relapsing RR-MS patients. Moreover, CD39+ Tregs were significantly correlated with the EDSS score and were independently associated with the odds of RR-MS. Our results highlight the relevance of CD39+ Treg subset in the clinical outcomes of RR-MS.

Highlights

The pathogenesis of multiple sclerosis (MS), a chronic neuroinflammatory disease of the central nervous system (CNS), includes both inflammatory and neurodegenerative mechanisms which are triggered by the infiltration of myelin-specific CD4+ T helper (Th) cells
peripheral blood mononuclear cells (PBMCs) from patients and controls were incubated with ATP and the ecto-ATPase activity was assessed by measuring the amount of inorganic phosphate released in culture supernatants
CD39 mRNA expression was not found to be altered in PBMCs from either relapsing-remitting MS (RR-MS) patients who were treated with immunomodulatory drugs or those who were not treated, compared with controls (Fig. 2a–c)

Summary

Introduction

The pathogenesis of multiple sclerosis (MS), a chronic neuroinflammatory disease of the central nervous system (CNS), includes both inflammatory and neurodegenerative mechanisms which are triggered by the infiltration of myelin-specific CD4+ T helper (Th) cells. During MS exacerbations, the CD39 mRNA levels in PBMCs and CD39+ cell frequency within Tregs show either no differences[16,18] or an increase[19] in comparison with controls. Different immunomodulatory treatments such as interferon (IFN) β, fingolimod, alemtuzumab and corticoids have been reported to increase the expression and levels of CD39, the frequency of CD39+ Treg cells, and the ATP/ADP hydrolysis capacity of those cells[15,17,19,20,21,22]. The objective of our work was to analyse the expression of CD39 in PBMCs from relapsing RR-MS patients and age- and sex-paired healthy subjects, with a special focus on the expression of CD39 on Treg cells

Objectives

Methods

Results

Conclusion