Partial MHC class II constructs inhibit MIF/CD74 binding and downstream effects (P5221)

• Published in: The Journal of immunology (1950) Vol. 190; no. Supplement_1; pp. 67 - 67.4
• Main Authors: Benedek, Gil, Meza-Romero, Roberto, Andrew, Shayne, Leng, Lin, Burrows, Gregory, Bourdette, Dennis, Offner, Halina, Bucala, Richard, Vandenbark, Arthur
• Format: Journal Article
• Language: English
• Published: 01.05.2013
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.190.Supp.67.4

Macrophage migration inhibitory factor (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 beta 1 alpha 1 domains with covalently attached antigenic peptides (also referred to as recombinant T cell receptor ligands - RTL) can inhibit MIF activity by not only blocking the binding of rhMIF to immunopurified CD74, but also down-regulating CD74 cell-surface expression. This bi-functional inhibition of MIF/CD74 interactions blocks downstream MIF effects, including enhanced secretion of proinflammatory cytokines, anti-apoptotic activity and inhibition of random migration that all contribute to reversal of clinical and histological signs of experimental autoimmune encephalomyelitis (EAE). Moreover, we demonstrate that enhanced CD74 cell surface expression on monocytes in mice with EAE and subjects with multiple sclerosis (MS) can be down-regulated by humanized RTL, 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.