title: Antigenic Stimulation of Kv1.3-Deficient Th Cells Gives Rise to a Population of Foxp3-Independent T Cells with Suppressive Properties.
abstract: Multiple sclerosis (MS) is an immune-mediated demyelinating disease of the CNS that has been linked with defects in regulatory T cell function. Therefore, strategies to selectively target pathogenic cells via enhanced regulatory T cell activity may provide therapeutic benefit. Kv1.3 is a voltage-gated potassium channel expressed on myelin-reactive T cells from MS patients. Kv1.3-knockout (KO) mice are protected from experimental autoimmune encephalomyelitis, an animal model of MS, and Kv1.3-KO Th cells display suppressive capacity associated with increased IL-10. In this article, we demonstrate that myelin oligodendrocyte glycoprotein-specific Kv1.3-KO Th cells exhibit a unique regulatory phenotype characterized by high CD25, CTLA4, pSTAT5, FoxO1, and GATA1 expression without a corresponding increase in Foxp3. These phenotypic changes result from increased signaling through IL-2R. Moreover, myelin oligodendrocyte glycoprotein-specific Kv1.3-KO Th cells can ameliorate experimental autoimmune encephalomyelitis following transfer to wild-type recipients in a manner that is partially dependent on IL-2R and STAT5 signaling. The present study identifies a population of Foxp3(-) T cells with suppressive properties that arises in the absence of Kv1.3 and enhances the understanding of the molecular mechanism by which these cells are generated. This increased understanding could contribute to the development of novel therapies for MS patients that promote heightened immune regulation.
authors.affiliation: Department of Neurology, The Johns Hopkins University School of Medicine, 600 North Wolfe Street, Baltimore, MD, USA.
authors.forename: Inna V
authors.initials: IV
authors.lastname: Grishkan
authors.affiliation: Department of Neurology, The Johns Hopkins University School of Medicine, 600 North Wolfe Street, Baltimore, MD, USA.
authors.forename: Dominique M
authors.initials: DM
authors.lastname: Tosi
authors.affiliation: Department of Neurology, The Johns Hopkins University School of Medicine, 600 North Wolfe Street, Baltimore, MD, USA.
authors.forename: Melissa D
authors.initials: MD
authors.lastname: Bowman
authors.affiliation: Department of Neurology, The Johns Hopkins University School of Medicine, 600 North Wolfe Street, Baltimore, MD, USA.
authors.forename: Maya
authors.initials: M
authors.lastname: Harary
authors.affiliation: Department of Neurology, The Johns Hopkins University School of Medicine, 600 North Wolfe Street, Baltimore, MD, USA.
authors.forename: Peter A
authors.initials: PA
authors.lastname: Calabresi
authors.affiliation: Department of Neurology, The Johns Hopkins University School of Medicine, 600 North Wolfe Street, Baltimore, MD, USA.
authors.forename: Anne R
authors.initials: AR
authors.lastname: Gocke
mesh_terms: D000818:Animals; D000941:Antigens / Q000276:immunology*; D060908:CTLA-4 Antigen / Q000235:genetics / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D016207:Cytokines / Q000096:biosynthesis; D004195:Disease Models, Animal; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism*; D050982:GATA1 Transcription Factor / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression; D056747:Immunomodulation; D016130:Immunophenotyping; D053645:Interleukin-2 Receptor alpha Subunit / Q000235:genetics / Q000378:metabolism; D051664:Kv1.3 Potassium Channel / Q000172:deficiency*; D051379:Mice; D018345:Mice, Knockout; D009103:Multiple Sclerosis / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D063308:Myelin-Oligodendrocyte Glycoprotein / Q000276:immunology; D050778:NFATC Transcription Factors / Q000378:metabolism; D010641:Phenotype; D010766:Phosphorylation; D050799:STAT5 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism*; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology* / Q000378:metabolism*
chemical_list: D000941:Antigens; D060908:CTLA-4 Antigen; D016207:Cytokines; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; C467200:Foxo1 protein, mouse; C498833:Foxp3 protein, mouse; D050982:GATA1 Transcription Factor; D053645:Interleukin-2 Receptor alpha Subunit; D051664:Kv1.3 Potassium Channel; D063308:Myelin-Oligodendrocyte Glycoprotein; D050778:NFATC Transcription Factors; D050799:STAT5 Transcription Factor; D002118:Calcium