Faculty Collaboration Database

CCR5 susceptibility to ligand-mediated down-modulation differs between human T lymphocytes and myeloid cells. J Leukoc Biol 2015 Jul;98(1):59-71

Date

05/10/2015

Pubmed ID

25957306

Pubmed Central ID

PMC4560160

DOI

10.1189/jlb.2A0414-193RR

Scopus ID

2-s2.0-84934759891 (requires institutional sign-in at Scopus site)   25 Citations

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.

Author List

Fox JM, Kasprowicz R, Hartley O, Signoret N

MESH terms used to index this publication - Major topics in bold

Animals
Antibodies, Monoclonal
Antigens
CHO Cells
Cricetinae
Cricetulus
Down-Regulation
Humans
Ligands
Microscopy, Fluorescence
Myeloid Cells
Protein Conformation
Receptors, CCR5
T-Lymphocytes