Partial MHC class II constructs inhibit MIF / CD 74 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: 01.05.2013
• ISSN: 0014-2980; 1521-4141
• DOI: 10.1002/eji.201243162

MIF and its receptor, CD 74, 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 — RTL s) can inhibit MIF activity by not only blocking the binding of rh MIF to immunopurified CD 74, but also downregulating CD 74 cell‐surface expression. This bifunctional inhibition of MIF / CD 74 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 CD 74 cell‐surface expression on monocytes in mice with EAE and subjects with multiple sclerosis can be downregulated by humanized RTL s, resulting in reduced MIF binding to the cells. Thus, binding of partial MHC complexes to CD 74 blocks both the accessibility and availability of CD 74 for MIF binding and downstream inflammatory activity.