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.