title: A novel regulatory pathway for autoimmune disease: binding of partial MHC class II constructs to monocytes reduces CD74 expression and induces both specific and bystander T-cell tolerance.
abstract: Treatment with partial (p)MHC class II-β1α1 constructs (also referred to as recombinant T-cell receptor ligands - RTL) linked to antigenic peptides can induce T-cell tolerance, inhibit recruitment of inflammatory cells and reverse autoimmune diseases. Here we demonstrate a novel regulatory pathway that involves RTL binding to CD11b(+) mononuclear cells through a receptor comprised of MHC class II invariant chain (CD74), cell-surface histones and MHC class II itself for treatment of experimental autoimmune encephalomyelitis (EAE). Binding of RTL constructs with CD74 involved a previously unrecognized MHC class II-α1/CD74 interaction that inhibited CD74 expression, blocked activity of its ligand, macrophage migration inhibitory factor, and reduced EAE severity. These findings implicate binding of RTL constructs to CD74 as a key step in both antigen-driven and bystander T-cell tolerance important in treatment of inflammatory diseases.
authors.affiliation: Research Service, Department of Veterans Affairs Medical Center, Portland, OR 97239, USA.|Neuroimmunology Research, Department of Veterans Affairs Medical Center, Portland, OR 97239, USA.|Tykeson MS Research Laboratory, UHS-46, 3181 SW Sam Jackson Park Rd, Oregon Health & Science University, Portland, OR 97239, USA.|Department of Neurology, Oregon Health & Science University, Portland, OR 97239, USA.|Department of Molecular Microbiology & Immunology, Oregon Health & Science University, Portland, OR 97239, USA.
authors.forename: Arthur A
authors.initials: AA
authors.lastname: Vandenbark
authors.affiliation: Neuroimmunology Research, Department of Veterans Affairs Medical Center, Portland, OR 97239, USA.|Tykeson MS Research Laboratory, UHS-46, 3181 SW Sam Jackson Park Rd, Oregon Health & Science University, Portland, OR 97239, USA.
authors.forename: Roberto
authors.initials: R
authors.lastname: Meza-Romero
authors.affiliation: Neuroimmunology Research, Department of Veterans Affairs Medical Center, Portland, OR 97239, USA.|Tykeson MS Research Laboratory, UHS-46, 3181 SW Sam Jackson Park Rd, Oregon Health & Science University, Portland, OR 97239, USA.|Department of Neurology, Oregon Health & Science University, Portland, OR 97239, USA.
authors.forename: Gil
authors.initials: G
authors.lastname: Benedek
authors.affiliation: Neuroimmunology Research, Department of Veterans Affairs Medical Center, Portland, OR 97239, USA.|Tykeson MS Research Laboratory, UHS-46, 3181 SW Sam Jackson Park Rd, Oregon Health & Science University, Portland, OR 97239, USA.
authors.forename: Shayne
authors.initials: S
authors.lastname: Andrew
authors.affiliation: Tykeson MS Research Laboratory, UHS-46, 3181 SW Sam Jackson Park Rd, Oregon Health & Science University, Portland, OR 97239, USA.
authors.forename: Jianya
authors.initials: J
authors.lastname: Huan
authors.affiliation: Tykeson MS Research Laboratory, UHS-46, 3181 SW Sam Jackson Park Rd, Oregon Health & Science University, Portland, OR 97239, USA.|Department of Neurology, Oregon Health & Science University, Portland, OR 97239, USA.
authors.forename: Yuan K
authors.initials: YK
authors.lastname: Chou
authors.affiliation: Tykeson MS Research Laboratory, UHS-46, 3181 SW Sam Jackson Park Rd, Oregon Health & Science University, Portland, OR 97239, USA.
authors.forename: Abigail C
authors.initials: AC
authors.lastname: Buenafe
authors.affiliation: Faculty of Biology, Technion-Israel Institute of Technology, Haifa, Israel.
authors.forename: Rony
authors.initials: R
authors.lastname: Dahan
authors.affiliation: Faculty of Biology, Technion-Israel Institute of Technology, Haifa, Israel.
authors.forename: Yoram
authors.initials: Y
authors.lastname: Reiter
authors.affiliation: Tykeson MS Research Laboratory, UHS-46, 3181 SW Sam Jackson Park Rd, Oregon Health & Science University, Portland, OR 97239, USA.
authors.forename: Jeffery L
authors.initials: JL
authors.lastname: Mooney
authors.affiliation: Neuroimmunology Research, Department of Veterans Affairs Medical Center, Portland, OR 97239, USA.|Department of Neurology, Oregon Health & Science University, Portland, OR 97239, USA.|Department of Anesthesiology and Perioperative Medicine, Oregon Health & Science University, Portland, OR 97239, USA.
authors.forename: Halina
authors.initials: H
authors.lastname: Offner
authors.affiliation: Tykeson MS Research Laboratory, UHS-46, 3181 SW Sam Jackson Park Rd, Oregon Health & Science University, Portland, OR 97239, USA.|Department of Neurology, Oregon Health & Science University, Portland, OR 97239, USA.|Department of Biochemistry, Oregon Health & Science University, Portland, OR 97239, USA.|Hematology & Medical Oncology, Knight Cancer Institute, Oregon Health & Science University, Portland, OR 97239, USA.
authors.forename: Gregory G
authors.initials: GG
authors.lastname: Burrows
mesh_terms: D000818:Animals; D000944:Antigens, Differentiation, B-Lymphocyte / Q000096:biosynthesis / Q000378:metabolism*; D001327:Autoimmune Diseases / Q000276:immunology*; D039481:CD11b Antigen / Q000378:metabolism; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology; D000949:Histocompatibility Antigens Class II / Q000096:biosynthesis / Q000276:immunology / Q000378:metabolism*; D007108:Immune Tolerance; D019746:Intramolecular Oxidoreductases; D008263:Macrophage Migration-Inhibitory Factors; D008565:Membrane Proteins; D051379:Mice; D009000:Monocytes / Q000276:immunology*; D011948:Receptors, Antigen, T-Cell; D011993:Recombinant Fusion Proteins / Q000276:immunology / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology
chemical_list: D000944:Antigens, Differentiation, B-Lymphocyte; D039481:CD11b Antigen; D000949:Histocompatibility Antigens Class II; D008263:Macrophage Migration-Inhibitory Factors; D008565:Membrane Proteins; C571058:RTL342M protein, mouse; D011948:Receptors, Antigen, T-Cell; D011993:Recombinant Fusion Proteins; C045084:invariant chain; D019746:Intramolecular Oxidoreductases; C076231:Mif protein, mouse