title: TLR2 stimulation regulates the balance between regulatory T cell and Th17 function: a novel mechanism of reduced regulatory T cell function in multiple sclerosis.
abstract: CD4(+)CD25(hi) FOXP3(+) regulatory T cells (Tregs) maintain tolerance to self-Ags. Their defective function is involved in the pathogenesis of multiple sclerosis (MS), an inflammatory demyelinating disease of the CNS. However, the mechanisms of such defective function are poorly understood. Recently, we reported that stimulation of TLR2, which is preferentially expressed by human Tregs, reduces their suppressive function and skews them into a Th17-like phenotype. In this study, we tested the hypothesis that TLR2 activation is involved in reduced Treg function in MS. We found that Tregs from MS patients expressed higher levels of TLR2 compared with healthy controls, and stimulation with the synthetic lipopeptide Pam3Cys, an agonist of TLR1/2, reduced Treg function and induced Th17 skewing in MS patient samples more than in healthy controls. These data provide a novel mechanism underlying diminished Treg function in MS. Infections that activate TLR2 in vivo (specifically through TLR1/2 heterodimers) could shift the Treg/Th17 balance toward a proinflammatory state in MS, thereby promoting disease activity and progression.
authors.affiliation: Clinical Neurology Research Group, Division of Clinical Neuroscience, University of Nottingham School of Medicine, Nottingham NG7 2UH, United Kingdom; Neuroimmunology Unit, Montreal Neurological Institute, McGill University, Montreal, Quebec H3A 2B4, Canada;
authors.forename: Mukanthu H
authors.initials: MH
authors.lastname: Nyirenda
authors.affiliation: Clinical Neurology Research Group, Division of Clinical Neuroscience, University of Nottingham School of Medicine, Nottingham NG7 2UH, United Kingdom;
authors.forename: Elena
authors.initials: E
authors.lastname: Morandi
authors.affiliation: School of Life Sciences, University of Nottingham School of Medicine, Nottingham NG7 2UH, United Kingdom; and.
authors.forename: Uwe
authors.initials: U
authors.lastname: Vinkemeier
authors.affiliation: School of Life Sciences, University of Nottingham School of Medicine, Nottingham NG7 2UH, United Kingdom; and.
authors.forename: Dumitru
authors.initials: D
authors.lastname: Constantin-Teodosiu
authors.affiliation: Clinical Neurology Research Group, Division of Clinical Neuroscience, University of Nottingham School of Medicine, Nottingham NG7 2UH, United Kingdom;
authors.forename: Sophie
authors.initials: S
authors.lastname: Drinkwater
authors.affiliation: School of Life Sciences, University of Nottingham School of Medicine, Nottingham NG7 2UH, United Kingdom; and.
authors.forename: Maureen
authors.initials: M
authors.lastname: Mee
authors.affiliation: Clinical Neurology Research Group, Division of Clinical Neuroscience, University of Nottingham School of Medicine, Nottingham NG7 2UH, United Kingdom;
authors.forename: Lloyd
authors.initials: L
authors.lastname: King
authors.affiliation: Clinical Neurology Research Group, Division of Clinical Neuroscience, University of Nottingham School of Medicine, Nottingham NG7 2UH, United Kingdom;
authors.forename: Giulio
authors.initials: G
authors.lastname: Podda
authors.affiliation: Department of Neurology, Thomas Jefferson University, Philadelphia, PA 19107.
authors.forename: Guang-Xian
authors.initials: GX
authors.lastname: Zhang
authors.affiliation: School of Life Sciences, University of Nottingham School of Medicine, Nottingham NG7 2UH, United Kingdom; and.
authors.forename: Amir
authors.initials: A
authors.lastname: Ghaemmaghami
authors.affiliation: Clinical Neurology Research Group, Division of Clinical Neuroscience, University of Nottingham School of Medicine, Nottingham NG7 2UH, United Kingdom;
authors.forename: Cris S
authors.initials: CS
authors.lastname: Constantinescu
authors.affiliation: Neuroimmunology Unit, Montreal Neurological Institute, McGill University, Montreal, Quebec H3A 2B4, Canada;
authors.forename: Amit
authors.initials: A
authors.lastname: Bar-Or
authors.affiliation: Clinical Neurology Research Group, Division of Clinical Neuroscience, University of Nottingham School of Medicine, Nottingham NG7 2UH, United Kingdom; bruno.gran@nottingham.ac.uk.
authors.forename: Bruno
authors.identifier: http://orcid.org/0000-0001-6384-2342
authors.initials: B
authors.lastname: Gran
mesh_terms: D000328:Adult; D016022:Case-Control Studies; D002454:Cell Differentiation / Q000187:drug effects; D016207:Cytokines / Q000096:biosynthesis; D005260:Female; D006801:Humans; D056747:Immunomodulation; D016130:Immunophenotyping; D008074:Lipoproteins / Q000494:pharmacology; D008297:Male; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000276:immunology* / Q000378:metabolism*; D020529:Multiple Sclerosis, Relapsing-Remitting / Q000276:immunology / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism; D016176:T-Lymphocyte Subsets / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000276:immunology* / Q000378:metabolism*; D058504:Th17 Cells / Q000166:cytology / Q000276:immunology* / Q000378:metabolism*; D051195:Toll-Like Receptor 2 / Q000819:agonists / Q000378:metabolism*; D055815:Young Adult
chemical_list: D016207:Cytokines; D008074:Lipoproteins; D050796:STAT3 Transcription Factor; D051195:Toll-Like Receptor 2; C061108:N-palmitoyl-S-(2,3-bis(palmitoyloxy)propyl)cysteinyl-seryl-lysyl-lysyl-lysyl-lysine