期刊
EUROPEAN JOURNAL OF IMMUNOLOGY
卷 43, 期 5, 页码 1309-1321出版社
WILEY-BLACKWELL
DOI: 10.1002/eji.201243162
关键词
CD74; Macrophage migration inhibitory factor (MIF); Multiple sclerosis; Recombinant T-cell receptor ligand
类别
资金
- NIH [NS47661, AR050498]
- National Multiple Sclerosis Society [RG3794-B-6]
- Oregon Medical Research Foundation
- Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development, Biomedical Laboratory Research and Development
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 11 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.
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