title: Partial MHC class II constructs inhibit MIF/CD74 binding and downstream effects.
abstract: MIF and its receptor, CD74, are pivotal regulators of the immune system. Here, we demonstrate for the first time that partial MHC class II constructs comprised of linked β1α1 domains with covalently attached antigenic peptides (also referred to as recombinant T-cell receptor ligands - RTLs) can inhibit MIF activity by not only blocking the binding of rhMIF to immunopurified CD74, but also downregulating CD74 cell-surface expression. This bifunctional inhibition of MIF/CD74 interactions blocked downstream MIF effects, including enhanced secretion of proinflammatory cytokines, anti-apoptotic activity, and inhibition of random migration that all contribute to the reversal of clinical and histological signs of EAE. Moreover, we demonstrate that enhanced CD74 cell-surface expression on monocytes in mice with EAE and subjects with multiple sclerosis can be downregulated by humanized RTLs, resulting in reduced MIF binding to the cells. Thus, binding of partial MHC complexes to CD74 blocks both the accessibility and availability of CD74 for MIF binding and downstream inflammatory activity.
authors.affiliation: Department of Veterans Affairs Medical Center, Neuroimmunology Research, Portland, OR 97239, USA.
authors.forename: Gil
authors.initials: G
authors.lastname: Benedek
authors.forename: Roberto
authors.initials: R
authors.lastname: Meza-Romero
authors.forename: Shayne
authors.initials: S
authors.lastname: Andrew
authors.forename: Lin
authors.initials: L
authors.lastname: Leng
authors.forename: Gregory G
authors.initials: GG
authors.lastname: Burrows
authors.forename: Dennis
authors.initials: D
authors.lastname: Bourdette
authors.forename: Halina
authors.initials: H
authors.lastname: Offner
authors.forename: Richard
authors.initials: R
authors.lastname: Bucala
authors.forename: Arthur A
authors.initials: AA
authors.lastname: Vandenbark
mesh_terms: D000818:Animals; D000944:Antigens, Differentiation, B-Lymphocyte / Q000235:genetics / Q000276:immunology*; D002465:Cell Movement / Q000187:drug effects; D016207:Cytokines / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D005786:Gene Expression Regulation / Q000187:drug effects; D000949:Histocompatibility Antigens Class II / Q000235:genetics / Q000276:immunology / Q000494:pharmacology*; D006801:Humans; D019746:Intramolecular Oxidoreductases / Q000235:genetics / Q000276:immunology*; D008024:Ligands; D008263:Macrophage Migration-Inhibitory Factors / Q000235:genetics / Q000276:immunology*; D051379:Mice; D009103:Multiple Sclerosis / Q000188:drug therapy / Q000276:immunology / Q000473:pathology; D010455:Peptides / Q000235:genetics / Q000276:immunology / Q000494:pharmacology*; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000276:immunology; D011994:Recombinant Proteins / Q000235:genetics / Q000276:immunology / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D000944:Antigens, Differentiation, B-Lymphocyte; D016207:Cytokines; D000949:Histocompatibility Antigens Class II; D008024:Ligands; D008263:Macrophage Migration-Inhibitory Factors; D010455:Peptides; D011948:Receptors, Antigen, T-Cell; D011994:Recombinant Proteins; C045084:invariant chain; D019746:Intramolecular Oxidoreductases; C515598:MIF protein, human; C076231:Mif protein, mouse