CCR5 HAS AN EXPANDED LIGAND-BINDING REPERTOIRE AND IS THE PRIMARY RECEPTOR USED BY MCP-2 ON ACTIVATED T-CELLS

CCR5 is a chemokine receptor expressed by T cells and macrophages, whi ch also functions as the principal coreceptor for macrophage (M)-tropi c HIV-1 strains to enter the host cells. In this study, we aim to bett er understand the ligand-binding profiles of CCR5 and the chemokine-re ceptor usage on leukocyte cells. We found that MCP-2 could bind to CCR 5 transfectants with high affinity and cross-compete effectively with RANTES, MIP-1 alpha, and MIP-1 beta. 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-desensit ization with RANTES in the Ca2+ flux response. MCP-4 also bound to CCR 5 with high affinity and was efficiently displaced by other CCR5 ligan ds. However, MCP-4 only partially displaced the binding of radiolabele d MIP-1 alpha and caused a chemotactic response only at high concentra tions. 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 b ind and elicit chemotaxis in CD3-activated and IL-2-maintained T cells , and most of these functions could be specifically inhibited by the a nti-CCR5 mAb 2D7, whereas the responses mediated by MIP-1 alpha 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 an d CCR5 are expressed at high levels on activated T cells, it appears t o preferably utilize CCR5 on these cells. In contrast, MIP-1 alpha and MCP-4 seem to activate multiple receptors on the same cells. (C) 1998 Academic Press.