title: CCR5 susceptibility to ligand-mediated down-modulation differs between human T lymphocytes and myeloid cells.
abstract: CCR5 is a chemokine receptor expressed on leukocytes and a coreceptor used by HIV-1 to enter CD4(+) T lymphocytes and macrophages. Stimulation of CCR5 by chemokines triggers internalization of chemokine-bound CCR5 molecules in a process called down-modulation, which contributes to the anti-HIV activity of chemokines. Recent studies have shown that CCR5 conformational heterogeneity influences chemokine-CCR5 interactions and HIV-1 entry in transfected cells or activated CD4(+) T lymphocytes. However, the effect of CCR5 conformations on other cell types and on the process of down-modulation remains unclear. We used mAbs, some already shown to detect distinct CCR5 conformations, to compare the behavior of CCR5 on in vitro generated human T cell blasts, monocytes and MDMs and CHO-CCR5 transfectants. All human cells express distinct antigenic forms of CCR5 not detected on CHO-CCR5 cells. The recognizable populations of CCR5 receptors exhibit different patterns of down-modulation on T lymphocytes compared with myeloid cells. On T cell blasts, CCR5 is recognized by all antibodies and undergoes rapid chemokine-mediated internalization, whereas on monocytes and MDMs, a pool of CCR5 molecules is recognized by a subset of antibodies and is not removed from the cell surface. We demonstrate that this cell surface-retained form of CCR5 responds to prolonged treatment with more-potent chemokine analogs and acts as an HIV-1 coreceptor. Our findings indicate that the regulation of CCR5 is highly specific to cell type and provide a potential explanation for the observation that native chemokines are less-effective HIV-entry inhibitors on macrophages compared with T lymphocytes.
authors.affiliation: *Department of Biology and Hull York Medical School, Center for Immunology and Infection, University of York, York, United Kingdom; and Department of Pathology and Immunology, University of Geneva, Geneva, Switzerland.
authors.forename: James M
authors.initials: JM
authors.lastname: Fox
authors.affiliation: *Department of Biology and Hull York Medical School, Center for Immunology and Infection, University of York, York, United Kingdom; and Department of Pathology and Immunology, University of Geneva, Geneva, Switzerland.
authors.forename: Richard
authors.initials: R
authors.lastname: Kasprowicz
authors.affiliation: *Department of Biology and Hull York Medical School, Center for Immunology and Infection, University of York, York, United Kingdom; and Department of Pathology and Immunology, University of Geneva, Geneva, Switzerland.
authors.forename: Oliver
authors.initials: O
authors.lastname: Hartley
authors.affiliation: *Department of Biology and Hull York Medical School, Center for Immunology and Infection, University of York, York, United Kingdom; and Department of Pathology and Immunology, University of Geneva, Geneva, Switzerland nathalie.signoret@york.ac.uk.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Signoret
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D000941:Antigens / Q000097:blood; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D015536:Down-Regulation; D006801:Humans; D008024:Ligands; D008856:Microscopy, Fluorescence; D022423:Myeloid Cells / Q000378:metabolism*; D011487:Protein Conformation; D019713:Receptors, CCR5 / Q000276:immunology / Q000378:metabolism / Q000502:physiology*; D013601:T-Lymphocytes / Q000378:metabolism*
chemical_list: D000911:Antibodies, Monoclonal; D000941:Antigens; C584933:CCR5 protein, human; D008024:Ligands; D019713:Receptors, CCR5
keywords: HIV-1; Internalization; chemokine receptor; monocytes/macrophages