title: Multiple sclerosis associated genetic variants of CD226 impair regulatory T cell function.
abstract: Recent association studies have linked numerous genetic variants with an increased risk for multiple sclerosis, although their functional relevance remains largely unknown. Here we investigated phenotypical and functional consequences of a genetic variant in the CD226 gene that, among other autoimmune diseases, predisposes to multiple sclerosis. Phenotypically, effector and regulatory CD4(+) memory T cells of healthy individuals carrying the predisposing CD226 genetic variant showed, in comparison to carriers of the protective variant, reduced surface expression of CD226 and an impaired induction of CD226 after stimulation. This haplotype-dependent reduction in CD226 expression on memory T cells was abrogated in patients with multiple sclerosis, as CD226 expression was comparable to healthy risk haplotype carriers irrespective of genetic variant. Functionally, FOXP3-positive regulatory T cells from healthy carriers of the genetic protective variant showed superior suppressive capacity, which was again abrogated in multiple sclerosis patients. Mimicking the phenotype of human CD226 genetic risk variant carriers, regulatory T cells derived from Cd226-deficient mice showed similarly reduced inhibitory activity, eventually resulting in an exacerbated disease course of experimental autoimmune encephalomyelitis, the animal model of multiple sclerosis. Therefore, by combining human and mouse analyses we show that CD226 exhibits an important role in the activation of regulatory T cells, with its genetically imposed dysregulation impairing regulatory T cell function.
authors.affiliation: Institut für Neuroimmunologie und Multiple Sklerose, Zentrum für Molekulare Neurobiologie Hamburg, Universitätsklinikum Hamburg-Eppendorf, Hamburg, Germany manuel.friese@zmnh.uni-hamburg.de.
authors.forename: Melanie
authors.initials: M
authors.lastname: Piédavent-Salomon
authors.affiliation: Institut für Neuroimmunologie und Multiple Sklerose, Zentrum für Molekulare Neurobiologie Hamburg, Universitätsklinikum Hamburg-Eppendorf, Hamburg, Germany manuel.friese@zmnh.uni-hamburg.de.
authors.forename: Anne
authors.initials: A
authors.lastname: Willing
authors.affiliation: Institut für Neuroimmunologie und Multiple Sklerose, Zentrum für Molekulare Neurobiologie Hamburg, Universitätsklinikum Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Jan Broder
authors.initials: JB
authors.lastname: Engler
authors.affiliation: Institut für Neuroimmunologie und Multiple Sklerose, Zentrum für Molekulare Neurobiologie Hamburg, Universitätsklinikum Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Karin
authors.initials: K
authors.lastname: Steinbach
authors.affiliation: Institut für Neuroimmunologie und Multiple Sklerose, Zentrum für Molekulare Neurobiologie Hamburg, Universitätsklinikum Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Simone
authors.initials: S
authors.lastname: Bauer
authors.affiliation: Institut für Neuroimmunologie und Multiple Sklerose, Zentrum für Molekulare Neurobiologie Hamburg, Universitätsklinikum Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Britta
authors.initials: B
authors.lastname: Eggert
authors.affiliation: Institut für Neuroimmunologie und Multiple Sklerose, Zentrum für Molekulare Neurobiologie Hamburg, Universitätsklinikum Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Friederike
authors.initials: F
authors.lastname: Ufer
authors.affiliation: Institut für Neuroimmunologie und Multiple Sklerose, Zentrum für Molekulare Neurobiologie Hamburg, Universitätsklinikum Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Nina
authors.initials: N
authors.lastname: Kursawe
authors.affiliation: Institut für Neuroimmunologie und Multiple Sklerose, Zentrum für Molekulare Neurobiologie Hamburg, Universitätsklinikum Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Sabine
authors.initials: S
authors.lastname: Wehrmann
authors.affiliation: Institut für Neuroimmunologie und Multiple Sklerose, Zentrum für Molekulare Neurobiologie Hamburg, Universitätsklinikum Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Jan
authors.initials: J
authors.lastname: Jäger
authors.affiliation: Institut für Neuroimmunologie und Multiple Sklerose, Zentrum für Molekulare Neurobiologie Hamburg, Universitätsklinikum Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Reinhardt
authors.affiliation: Institut für Neuroimmunologie und Multiple Sklerose, Zentrum für Molekulare Neurobiologie Hamburg, Universitätsklinikum Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Manuel A
authors.initials: MA
authors.lastname: Friese
mesh_terms: D000328:Adult; D000818:Animals; D000945:Antigens, Differentiation, T-Lymphocyte / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000235:genetics; D005260:Female; D051858:Forkhead Transcription Factors / Q000378:metabolism; D020022:Genetic Predisposition to Disease; D006239:Haplotypes; D006579:Heterozygote; D006801:Humans; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D012333:RNA, Messenger / Q000378:metabolism*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism; D000098862:T Lineage-Specific Activation Antigen 1
chemical_list: D000945:Antigens, Differentiation, T-Lymphocyte; D000098862:T Lineage-Specific Activation Antigen 1; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D012333:RNA, Messenger
keywords: CD226; autoimmunity; multiple sclerosis; regulatory T cells