A fusion protein encoding the second extracellular domain of CCR5 arrests chemokine-induced cosignaling and effectively suppresses ongoing experimental autoimmune encephalomyelitis.
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 these ligands, such as TNF-alpha, IL-17, and IFN-gamma production, are CCR5 independent and therefore likely to be mediated by the other receptors for these ligands. These findings imply that implementing a CCR5-Ig-based therapy would be advantageous over blockade of this receptor or of the use of mAbs for targeting a single CCR5 ligand.
Sapir
Yair
Y
Department of Immunology, Bruce Rappaport Faculty of Medicine, Technion, Haifa, Israel.
Vitenshtein
Alon
A
Barsheshet
Yiftah
Y
Zohar
Yaniv
Y
Wildbaum
Gizi
G
Karin
Nathan
N
D000818:Animals; D001665:Binding Sites / Q000235:genetics; D049109:Cell Proliferation; D002478:Cells, Cultured; D018925:Chemokines / Q000276:immunology* / Q000378:metabolism; D016207:Cytokines / Q000276:immunology / Q000378:metabolism; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology* / Q000473:pathology / Q000517:prevention & control; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005434:Flow Cytometry; D007136:Immunoglobulins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011485:Protein Binding; D019713:Receptors, CCR5 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000276:immunology* / Q000378:metabolism / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism
D018925:Chemokines; D016207:Cytokines; D007136:Immunoglobulins; D019713:Receptors, CCR5; D011993:Recombinant Fusion Proteins