CCR5 susceptibility to ligand-mediated down-modulation differs between human T lymphocytes and myeloid cells. Issue 1 (8th May 2015)

• Record Type: Journal Article
• Authors: Fox, James M; Kasprowicz, Richard; Hartley, Oliver; Signoret, Nathalie
• Is Part Of: Journal of leukocyte biology. Volume 98:Issue 1(2015)
• Page Start: 59
• Page End: 71
• Publication Date: 2015-05-08
• Subjects: chemokine receptor -- Internalization -- monocytes/macrophages -- HIV-1; Leucocytes -- Periodicals; Reticulo-endothelial system -- Periodicals; 571.96
• DOI: 10.1189/jlb.2A0414-193RR
• Languages: English
• ISSNs: 0741-5400

Abstract

Abstract : The behavior of endogenous CCR5 receptors is influenced by the cellular context on primary human leukocytes. 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.