A fusion protein encoding the second extracellular domain of CCR5 arrests chemokine-induced cosignaling and effectively suppresses ongoing experimental autoimmune encephalomyelitis

The Journal of Immunology : Official Journal of the American Association of Immunologists
Yair SapirNathan Karin

Abstract

CCR5 is a key CCR that is highly expressed on CD4(+) T cells. It binds three different ligands: CCL3 (MIP-alpha), CCL4 (MIP-beta), and CCL5 (RANTES). Recent studies suggested that the interaction between CCR5 and its ligands is essential not only for attracting these CCR5(+) T cells but also substantial for transuding cosignals for their activation. The current study explores, for the first time, the in vivo consequences of CCR5 as a costimulatory molecule. First, we show redundancy between CCR5 ligands not only in chemoattractive properties but also in their ability to induced cosignals via CCR5. This has motivated us to generate a soluble receptor-based fusion protein that would selectively bind and neutralize all three CCR5 ligands. We show in this study that a 30-aa-based CCR5-Ig fusion protein encoding the second extracellular domain of receptor selectively binds and neutralizes all three CCR5 ligands and, when administered during ongoing experimental autoimmune encephalomyelitis, rapidly suppressed the disease while arresting Ag-specific effector T cell functions. Finally, our results clearly show that although CCR5 ligands induced cosignaling for IL-2 production is directed by CCR5, other proinflammatory properties of th...Continue Reading

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Citations

Feb 19, 2014·Expert Reviews in Molecular Medicine·Juan Antonio MorenoJesús Egido
Apr 10, 2014·The Journal of Clinical Investigation·Yaniv ZoharNathan Karin
Jan 20, 2016·Nature Reviews. Neurology·Guillaume Martin-BlondelRoland S Liblau
Apr 7, 2017·Cancer Immunology, Immunotherapy : CII·Viktor UmanskyJochen Utikal
Dec 15, 2015·Journal of Leukocyte Biology·Nathan KarinMarcus Thelen
Oct 26, 2016·Journal of Translational Medicine·Zongtang LiuChengshan Guo
Nov 2, 2017·Cancer Research·Carolin BlattnerViktor Umansky
Aug 20, 2019·Neurological Research and Practice·Maria-Ioanna StefanouMarkus C Kowarik

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