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, 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-1alpha, and MIP-1beta. 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-1alpha 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-1alpha 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-1alpha and MCP-4 seem to activate multiple receptors on the same cells.
Ruffing
N
N
LeukoSite, Inc., 215 First Street, Cambridge, Massachusetts, 02142, USA.
Sullivan
N
N
Sharmeen
L
L
Sodroski
J
J
Wu
L
L
D000818:Animals; D019556:COS Cells; D018946:Chemokine CCL5 / Q000494:pharmacology; D054412:Chemokine CCL8; D002634:Chemotaxis, Leukocyte; D015699:HIV Envelope Protein gp120 / Q000378:metabolism; D015497:HIV-1 / Q000502:physiology; D006801:Humans; D008213:Lymphocyte Activation; D051379:Mice; D018945:Monocyte Chemoattractant Proteins / Q000378:metabolism* / Q000494:pharmacology; D019713:Receptors, CCR5 / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D013601:T-Lymphocytes / Q000378:metabolism*
C099677:CCL13 protein, human; C515453:CCL8 protein, human; C515454:Ccl8 protein, mouse; D018946:Chemokine CCL5; D054412:Chemokine CCL8; D015699:HIV Envelope Protein gp120; D018945:Monocyte Chemoattractant Proteins; D019713:Receptors, CCR5