title: ORAI2 modulates store-operated calcium entry and T cell-mediated immunity.
abstract: Store-operated Ca2+entry (SOCE) through Ca2+release-activated Ca2+(CRAC) channels is critical for lymphocyte function and immune responses. CRAC channels are hexamers of ORAI proteins that form the channel pore, but the contributions of individual ORAI homologues to CRAC channel function are not well understood. Here we show that deletion of Orai1 reduces, whereas deletion of Orai2 increases, SOCE in mouse T cells. These distinct effects are due to the ability of ORAI2 to form heteromeric channels with ORAI1 and to attenuate CRAC channel function. The combined deletion of Orai1 and Orai2 abolishes SOCE and strongly impairs T cell function. In vivo, Orai1/Orai2 double-deficient mice have impaired T cell-dependent antiviral immune responses, and are protected from T cell-mediated autoimmunity and alloimmunity in models of colitis and graft-versus-host disease. Our study demonstrates that ORAI1 and ORAI2 form heteromeric CRAC channels, in which ORAI2 fine-tunes the magnitude of SOCE to modulate immune responses.
authors.affiliation: Experimental Pathology Program, Department of Pathology, New York University School of Medicine, 550 First Avenue, Smilow 316, New York, New York 10016, USA.
authors.forename: Martin
authors.initials: M
authors.lastname: Vaeth
authors.affiliation: Experimental Pathology Program, Department of Pathology, New York University School of Medicine, 550 First Avenue, Smilow 316, New York, New York 10016, USA.
authors.forename: Jun
authors.initials: J
authors.lastname: Yang
authors.affiliation: Department of Pharmacology, Northwestern University, Feinberg School of Medicine, Chicago, Illinois 60611, USA.
authors.forename: Megumi
authors.initials: M
authors.lastname: Yamashita
authors.affiliation: Experimental Pathology Program, Department of Pathology, New York University School of Medicine, 550 First Avenue, Smilow 316, New York, New York 10016, USA.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Zee
authors.affiliation: NYU College of Dentistry, New York University, New York, New York 10010, USA.
authors.forename: Miriam
authors.initials: M
authors.lastname: Eckstein
authors.affiliation: Experimental Pathology Program, Department of Pathology, New York University School of Medicine, 550 First Avenue, Smilow 316, New York, New York 10016, USA.
authors.forename: Camille
authors.initials: C
authors.lastname: Knosp
authors.affiliation: Experimental Pathology Program, Department of Pathology, New York University School of Medicine, 550 First Avenue, Smilow 316, New York, New York 10016, USA.
authors.forename: Ulrike
authors.initials: U
authors.lastname: Kaufmann
authors.affiliation: ImmunoGenes, Makkosi út 86, Budakeszi 2092, Hungary.
authors.forename: Peter
authors.initials: P
authors.lastname: Karoly Jani
authors.affiliation: NYU College of Dentistry, New York University, New York, New York 10010, USA.
authors.forename: Rodrigo S
authors.initials: RS
authors.lastname: Lacruz
authors.affiliation: Experimental and Clinical Pharmacology and Toxicology, School of Medicine, Saarland University, Homburg 66421, Germany.
authors.forename: Veit
authors.initials: V
authors.lastname: Flockerzi
authors.affiliation: ImmunoGenes, Makkosi út 86, Budakeszi 2092, Hungary.
authors.forename: Imre
authors.identifier: 0000-0002-0402-3862
authors.initials: I
authors.lastname: Kacskovics
authors.affiliation: Department of Pharmacology, Northwestern University, Feinberg School of Medicine, Chicago, Illinois 60611, USA.
authors.forename: Murali
authors.initials: M
authors.lastname: Prakriya
authors.affiliation: Experimental Pathology Program, Department of Pathology, New York University School of Medicine, 550 First Avenue, Smilow 316, New York, New York 10016, USA.
authors.forename: Stefan
authors.initials: S
authors.lastname: Feske
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D049109:Cell Proliferation; D003092:Colitis / Q000276:immunology / Q000473:pathology; D016207:Cytokines / Q000096:biosynthesis; D017353:Gene Deletion; D005786:Gene Expression Regulation; D006086:Graft vs Host Disease / Q000276:immunology / Q000473:pathology; D006706:Homeostasis; D006801:Humans; D007109:Immunity; D056724:Immunity, Humoral; D015640:Ion Channel Gating; D018655:Lymphocyte Count; D008264:Macrophages / Q000378:metabolism; D008807:Mice, Inbred BALB C; D000071740:ORAI1 Protein / Q000172:deficiency / Q000378:metabolism; D000071741:ORAI2 Protein / Q000172:deficiency / Q000378:metabolism*; D055503:Protein Multimerization; D013601:T-Lymphocytes / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000378:metabolism; D014184:Transplantation, Homologous
chemical_list: D016207:Cytokines; D000071740:ORAI1 Protein; D000071741:ORAI2 Protein; D002118:Calcium