CCR5 Has an Expanded Ligand-Binding Repertoire and Is the Primary Receptor Used by MCP-2 on Activated T Cells

• Published in: Cellular immunology 1998-11, Vol.189 (2), p.160-168
• Main Authors: Ruffing, Nancy, Sullivan, Nancy, Sharmeen, Lamia, Sodroski, Joseph, Wu, Lijun
• Format: Article
• Language: English
• Subjects: AIDS/HIV; Animals; Chemokine CCL5 - pharmacology; Chemokine CCL8; Chemotaxis, Leukocyte; COS Cells; HIV Envelope Protein gp120 - metabolism; HIV-1 - physiology; Humans; Lymphocyte Activation; Mice; Monocyte Chemoattractant Proteins - metabolism; Monocyte Chemoattractant Proteins - pharmacology; Receptors, CCR5 - metabolism; Signal Transduction - drug effects; T-Lymphocytes - metabolism
• ISSN: 0008-8749; 1090-2163
• DOI: 10.1006/cimm.1998.1379

CCR5 is a chemokine receptor expressed by T cells and macrophages, which also functions as the principal coreceptor for macrophage (M)-tropic HIV-1 strains to enter the host cells. In this study, we aim to better understand the ligand-binding profiles of CCR5 and the chemokine-receptor usage on leukocyte cells. We found that MCP-2 could bind to CCR5 transfectants with high affinity and cross-compete effectively with RANTES, MIP-1α, and MIP-1β. MCP-2 is a true agonist for CCR5, eliciting a robust chemotactic response in CCR5 transfectants similar to that of the three known CCR5 ligands and exhibiting cross-desensitization with RANTES in the Ca2+flux response. MCP-4 also bound to CCR5 with high affinity and was efficiently displaced by other CCR5 ligands. However, MCP-4 only partially displaced the binding of radiolabeled MIP-1α and caused a chemotactic response only at high concentrations. Furthermore, MCP-2 inhibited the binding of the M-tropic HIV-1 gp120 envelope glycoprotein to CCR5 and HIV-1 infection of peripheral blood mononuclear cells. More importantly, we found that MCP-2 could bind and elicit chemotaxis in CD3-activated and IL-2-maintained T cells, and most of these functions could be specifically inhibited by the anti-CCR5 mAb 2D7, whereas the responses mediated by MIP-1α or MCP-4 were only partially inhibited by 2D7. Thus, although MCP-2 can bind to and signal through CCR1, CCR2b, and CCR5, among which both CCR2 and CCR5 are expressed at high levels on activated T cells, it appears to preferably utilize CCR5 on these cells. In contrast, MIP-1α and MCP-4 seem to activate multiple receptors on the same cells.