title: Natural naive CD4+CD25+CD127low regulatory T cell (Treg) development and function are disturbed in multiple sclerosis patients: recovery of memory Treg homeostasis during disease progression.
abstract: 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(low)CD45RA(+) Tregs (nTregs) and their memory counterparts CD4(+)CD25(+)CD127(low)CD45RO(+) 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-beta 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.
authors.affiliation: Hasselt University, Biomedisch Onderzoeksinstituut and Transnationale Universiteit Limburg, School of Life Sciences, Diepenbeek, Belgium.
authors.forename: Koen
authors.initials: K
authors.lastname: Venken
authors.forename: Niels
authors.initials: N
authors.lastname: Hellings
authors.forename: Tom
authors.initials: T
authors.lastname: Broekmans
authors.forename: Karen
authors.initials: K
authors.lastname: Hensen
authors.forename: Jean-Luc
authors.initials: JL
authors.lastname: Rummens
authors.forename: Piet
authors.initials: P
authors.lastname: Stinissen
mesh_terms: D000328:Adult; D015703:Antigens, CD / Q000276:immunology; D002908:Chronic Disease; D018450:Disease Progression; D005260:Female; D006706:Homeostasis / Q000276:immunology*; D006801:Humans; D007156:Immunologic Memory; D008297:Male; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000276:immunology* / Q000473:pathology; D011948:Receptors, Antigen, T-Cell / Q000276:immunology; D020127:Recovery of Function / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000473:pathology; D013950:Thymus Gland / Q000276:immunology* / Q000473:pathology; D013997:Time Factors
chemical_list: D015703:Antigens, CD; D011948:Receptors, Antigen, T-Cell