Partial MHC class II constructs inhibit MIF/CD74 binding and downstream effects

• Published in: European journal of immunology Vol. 43; no. 5; pp. 1309 - 1321
• Main Authors: Benedek, Gil, Meza‐Romero, Roberto, Andrew, Shayne, Leng, Lin, Burrows, Gregory G., Bourdette, Dennis, Offner, Halina, Bucala, Richard, Vandenbark, Arthur A.
• Format: Journal Article
• Language: English
• Published: Germany Wiley Subscription Services, Inc 01.05.2013
• Subjects: Animals; Antigens, Differentiation, B-Lymphocyte - genetics; Antigens, Differentiation, B-Lymphocyte - immunology; CD74; Cell Movement - drug effects; Cytokines - antagonists & inhibitors; Cytokines - biosynthesis; Encephalomyelitis, Autoimmune, Experimental - drug therapy; Encephalomyelitis, Autoimmune, Experimental - immunology; Encephalomyelitis, Autoimmune, Experimental - pathology; Gene Expression Regulation - drug effects; Histocompatibility Antigens Class II - genetics; Histocompatibility Antigens Class II - immunology; Histocompatibility Antigens Class II - pharmacology; Humans; Immunology; Intramolecular Oxidoreductases - genetics; Intramolecular Oxidoreductases - immunology; Ligands; Macrophage migration inhibitory factor (MIF); Macrophage Migration-Inhibitory Factors - genetics; Macrophage Migration-Inhibitory Factors - immunology; Mice; Multiple sclerosis; Multiple Sclerosis - drug therapy; Multiple Sclerosis - immunology; Multiple Sclerosis - pathology; Peptides - genetics; Peptides - immunology; Peptides - pharmacology; Protein Binding; Protein Structure, Tertiary; Receptors, Antigen, T-Cell - genetics; Receptors, Antigen, T-Cell - immunology; Recombinant Proteins - genetics; Recombinant Proteins - immunology; Recombinant Proteins - pharmacology; Recombinant T‐cell receptor ligand; Signal Transduction - drug effects; T cell receptors
• ISSN: 0014-2980; 1521-4141; 1521-4141
• DOI: 10.1002/eji.201243162

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.