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Natural Naive CD4⁺CD25⁺CD127^low Regulatory T Cell (Treg) Development and Function Are Disturbed in Multiple Sclerosis Patients: Recovery of Memory Treg Homeostasis during Disease Progression¹

Koen Venken^*, Niels Hellings^*, Tom Broekmans^*,, Karen Hensen, Jean-Luc Rummens and Piet Stinissen^2,*

^* Hasselt University, Biomedisch Onderzoeksinstituut and Transnationale Universiteit Limburg, School of Life Sciences, Diepenbeek; Rehabilitation and Health Care Research Center, Department of Health Care, University College of the Province of Limburg, Hasselt; and Clinical Laboratory of Experimental Hematology, Virga Jesse Hospital, Hasselt, Belgium

Patients with relapsing-remitting multiple sclerosis (RR-MS) show a suboptimal CD4⁺CD25⁺ regulatory T cell (Treg) function, whereas no Treg alterations are observed in secondary progressive MS (SP-MS) patients. To clarify the difference in Treg activity between early and chronic disease stages in MS, we analyzed the functional capacity and homeostatic parameters of naive CD4⁺CD25⁺CD127^lowCD45RA⁺ Tregs (nTregs) and their memory counterparts CD4⁺CD25⁺CD127^lowCD45RO⁺ Tregs (mTregs) in untreated MS patients and healthy controls. Interestingly, whereas the suppressive capacity of FACS-sorted nTregs was impaired in both early and chronic MS patients, only the latter group showed a restored mTreg function. Consistent with this observation, chronic MS patients had increased numbers of mTregs as compared with age-matched early MS patients, whereas nTreg frequencies did not differ significantly. TCR excision circle numbers were reduced in nTregs of early MS patients, suggestive of a diminished nTreg thymic output. Moreover, a decreased number of CD31⁺ mTregs were observed in early vs chronic MS patients, indicating that inflammatory processes drive the homeostatic turnover of mTregs during the early disease stage. Additionally, early MS patients showed a more restricted nTreg and mTreg TCR BV gene profile as compared with healthy controls and chronic MS patients. Finally, analysis of IFN-β and glatiramer acetate-treated MS patients showed that these immunomodulatory drugs modify nTreg homeostasis. Taken together, this study provides strong evidence for a disturbed thymic nTreg development and function in MS patients. Moreover, memory Treg but not naive Treg homeostasis recovers during disease progression.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This study was supported by research funding from the Belgian Charchot Foundation, Hasselt University, and Transnational University Limburg.

² Address correspondence and reprint requests to Dr. Piet Stinissen, Hasselt University, Biomedisch Onderzoeksinstituut, Agoralaan, Building A, 3590 Diepenbeek, Belgium. E-mail address: piet.stinissen{at}uhasselt.be

³ Abbreviations used in this paper: Treg, CD4⁺CD25⁺ regulatory T cell; FOXP3, forkhead box P3; MS, multiple sclerosis; RR-MS, relapsing-remitting MS; SP-MS, secondary progressive MS; HC, healthy control; GA, glatiramer acetate; EDSS, Expanded Disability Status Scale; nTreg, CD4⁺CD25^highCD127^lowCD45RA⁺ naive Treg; mTreg, CD4⁺CD25^highCD127^lowCD45RO⁺ memory Treg; Tresp, responder T cell; TREC, T cell receptor excision circle; gDNA, genomic DNA; DD, disease duration; BV, V region of the β-chain.