TY - JOUR
T1 - Partial MHC class II constructs inhibit MIF/CD74 binding and downstream effects
AU - Benedek, Gil
AU - Meza-Romero, Roberto
AU - Andrew, Shayne
AU - Leng, Lin
AU - Burrows, Gregory G.
AU - Bourdette, Dennis
AU - Offner, Halina
AU - Bucala, Richard
AU - Vandenbark, Arthur A.
PY - 2013/4
Y1 - 2013/4
N2 - 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.
AB - 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.
KW - CD74
KW - Macrophage migration inhibitory factor (MIF)
KW - Multiple sclerosis
KW - Recombinant T-cell receptor ligand
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U2 - 10.1002/eji.201243162
DO - 10.1002/eji.201243162
M3 - Article
C2 - 23576302
AN - SCOPUS:84876824480
SN - 0014-2980
VL - 43
SP - 1309
EP - 1321
JO - European Journal of Immunology
JF - European Journal of Immunology
IS - 5
ER -