title: Selective ORAI1 Inhibition Ameliorates Autoimmune Central Nervous System Inflammation by Suppressing Effector but Not Regulatory T Cell Function.
abstract: The function of CD4(+) T cells is dependent on Ca(2+) influx through Ca(2+) release-activated Ca(2+) (CRAC) channels formed by ORAI proteins. To investigate the role of ORAI1 in proinflammatory Th1 and Th17 cells and autoimmune diseases, we genetically and pharmacologically modulated ORAI1 function. Immunization of mice lacking Orai1 in T cells with MOG peptide resulted in attenuated severity of experimental autoimmune encephalomyelitis (EAE). The numbers of T cells and innate immune cells in the CNS of ORAI1-deficient animals were strongly reduced along with almost completely abolished production of IL-17A, IFN-γ, and GM-CSF despite only partially reduced Ca(2+) influx. In Th1 and Th17 cells differentiated in vitro, ORAI1 was required for cytokine production but not the expression of Th1- and Th17-specific transcription factors T-bet and RORγt. The differentiation and function of induced regulatory T cells, by contrast, was independent of ORAI1. Importantly, induced genetic deletion of Orai1 in adoptively transferred, MOG-specific T cells was able to halt EAE progression after disease onset. Likewise, treatment of wild-type mice with a selective CRAC channel inhibitor after EAE onset ameliorated disease. Genetic deletion of Orai1 and pharmacological ORAI1 inhibition reduced the leukocyte numbers in the CNS and attenuated Th1/Th17 cell-mediated cytokine production. In human CD4(+) T cells, CRAC channel inhibition reduced the expression of IL-17A, IFN-γ, and other cytokines in a dose-dependent manner. Taken together, these findings support the conclusion that Th1 and Th17 cell function is particularly dependent on CRAC channels, which could be exploited as a therapeutic approach to T cell-mediated autoimmune diseases.
authors.affiliation: Department of Pathology, New York University School of Medicine, New York, NY 10016;
authors.forename: Ulrike
authors.initials: U
authors.lastname: Kaufmann
authors.affiliation: Department of Pathology, New York University School of Medicine, New York, NY 10016;
authors.forename: Patrick J
authors.initials: PJ
authors.lastname: Shaw
authors.affiliation: Department of Microbiology, New York University School of Medicine, New York, NY 10016;
authors.forename: Lina
authors.initials: L
authors.lastname: Kozhaya
authors.affiliation: Pharmacokinetics and Drug Metabolism, Amgen, Inc., Thousand Oaks, CA 91320;
authors.forename: Raju
authors.initials: R
authors.lastname: Subramanian
authors.affiliation: Inflammation Research, Amgen, Inc., Thousand Oaks, CA 91320; and.
authors.forename: Kevin
authors.initials: K
authors.lastname: Gaida
authors.affiliation: Department of Microbiology, New York University School of Medicine, New York, NY 10016;
authors.forename: Derya
authors.initials: D
authors.lastname: Unutmaz
authors.affiliation: Comparative Biology and Safety Sciences, Amgen, Inc., Thousand Oaks, CA 91320.
authors.forename: Helen J
authors.initials: HJ
authors.lastname: McBride
authors.affiliation: Department of Pathology, New York University School of Medicine, New York, NY 10016; feskes01@nyumc.org.
authors.forename: Stefan
authors.initials: S
authors.lastname: Feske
mesh_terms: D000818:Animals; D015220:Calcium Channels / Q000276:immunology*; D002469:Cell Separation; D002853:Chromatography, Liquid; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology* / Q000473:pathology; D005434:Flow Cytometry; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D000071740:ORAI1 Protein; D060888:Real-Time Polymerase Chain Reaction; D013116:Spinal Cord / Q000276:immunology / Q000473:pathology; D016176:T-Lymphocyte Subsets / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology; D053719:Tandem Mass Spectrometry; D018417:Th1 Cells / Q000276:immunology*; D058504:Th17 Cells / Q000276:immunology*
chemical_list: D015220:Calcium Channels; D000071740:ORAI1 Protein; C510746:ORAI1 protein, human; C520430:Orai1 protein, mouse