T Regulatory Cells Are Markers of Disease Activity in Multiple Sclerosis Patients

Dacia Dalla Libera,Carlo Avolio,Simona Galgani,Giancarlo Comi,Vittorio Martinelli,Diletta Di Mitri,Gianvito Martino,Alessandra Bergami,Maria Grazia Grasso,Roberto Furlan,Giovanna Borsellino,Diego Centonze,Luca Battistini,Claudio Gasperini,Federica Sallusto,Steven Jacobson

doi:10.1371/journal.pone.0021386

Abstract

FoxP3+ Treg cells are believed to play a role in the occurrence of autoimmunity and in the determination of clinical recurrences. Contradictory reports are, however, available describing frequency and function of Treg cells during autoimmune diseases. We examined, by both polychromatic flow cytometry, and real-time RT-PCR, several Treg markers in peripheral blood mononuclear cells from patients with multiple sclerosis (MS), an autoimmune disease affecting the central nervous system. We found that Tregs, as defined by CD25, CD39, FoxP3, CTLA4, and GITR expression, were significantly decreased in stable MS patients as compared to healthy donors, but, surprisingly, restored to normal levels during an acute clinical attack. We conclude that Treg cells are not involved in causing clinical relapses, but rather react to inflammation in the attempt to restore homeostasis.

Highlights

Cells with immunosuppressive functions raise particular interest in multiple sclerosis (MS) because of their potential role in pathogenesis, determination of disease course, and their prospective use in therapy [1]
The issue of T regulatory cells (Tregs) functionality is especially relevant since several studies have shown that CD4+CD25+ Treg cells are increased in inflammatory sites in autoimmunity
CD4+CD25+CD39+T cells co-express typical Treg markers CD4+CD25highCD39+ T cells are bona fide Treg cells, both those from healthy donors and from MS patients, displaying proliferation suppressive ability in classical in vitro assays [38]. In agreement with this model, when CD39+ T cells were compared to CD392 negative T cells, we found increased levels of expression of all Treg markers tested, namely Foxp3 (Fig. 1A), CTLA4 (Fig. 1B), and GITR (Fig. 1C)

Summary

Introduction

Cells with immunosuppressive functions raise particular interest in multiple sclerosis (MS) because of their potential role in pathogenesis, determination of disease course, and their prospective use in therapy [1]. Established markers of Treg functionality are lacking, polymorphisms in Tregs effector genes such as CTLA-4, GITR, FoxP3 have been linked to susceptibility to autoimmune diseases in humans, including MS [11,12]. GITR (glucocorticoid-induced tumour necrosis factor receptor), a member of the TNF receptor superfamily, is a surface receptor molecule involved in inhibiting the suppressive activity of Tregs. It is constitutively expressed in Tregs at a higher level than in other T cells recently activated T cells can upregulate GITR expression in humans [17,35]

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Conclusion