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Leukocyte Biology Section, National Heart and Lung Institute, Faculty of Medicine, Imperial College London, South Kensington Campus, London SW7 2AZ, United Kingdom
The chemokine receptor CXCR3 is expressed on the surface of both resting and activated T lymphocytes. We describe in this study the endocytosis of CXCR3 using T lymphocytes and CXCR3 transfectants. Chemokine-induced CXCR3 down-regulation occurred in a rapid, dose-dependent manner, with CXCL11 the most potent and efficacious ligand. Endocytosis was mediated in part by arrestins, but appeared to occur independently of clathrin and caveolae. In contrast to other chemokine receptors, which are largely recycled to the cell surface within an hour, cell surface replenishment of CXCR3 occurred over several hours and was dependent upon mRNA transcription, de novo protein synthesis, and transport through the endoplasmic reticulum and Golgi. Confocal microscopy and Western blotting confirmed the fate of endocytosed CXCR3 to be degradation, mediated in part by lysosomes and proteosomes. Site-directed mutagenesis of the CXCR3 C terminus revealed that internalization and degradation were independent of phosphorylation, ubiquitination, or a conserved LL motif. CXCR3 was found to be efficiently internalized in the absence of ligand, a process involving a YXXL motif at the extreme of the C terminus. Although freshly isolated T lymphocytes expressed moderate cell surface levels of CXCR3, they were only responsive to CXCL11 with CXCL9 and CXCL10 only having significant activity on activated T lymphocytes. Thus, the activities of CXCR3 are tightly controlled following mRNA translation. Because CXCR3+ cells are themselves a source of IFN-
, which potently induces the expression of CXCR3 ligands, such tight regulation of CXCR3 may serve as a control to avoid the unnecessary amplification of activated T lymphocyte recruitment.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by Grants PG/2000055 and FS/05/021 from the British Heart Foundation, Grant 174240 from the Arthritis Research Campaign, and Project Grant 076036/Z/04/Z from the Wellcome Trust.
2 A. Meiser and A. Mueller contributed equally to the study.
3 Current address: School of Chemical Sciences and Pharmacy, University of East Anglia, Norwich NR4 7TJ, U.K.
4 Address correspondence and reprint requests to Dr. James E. Pease, Leukocyte Biology Section, Faculty of Medicine, National Heart and Lung Institute, Sir Alexander Fleming Building, Imperial College London, South Kensington Campus, London SW7 2AZ, U.K. E-mail address: j.pease{at}imperial.ac.uk
5 Abbreviations used in this paper: GPCR, G protein-coupled receptor; HA, hemagglutinin; LAMP, lysosome-associated membrane protein; MEF, mouse embryonic fibroblast; ER, endoplasmic reticulum; WT, wild type.
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  M. Thapa and D. J. J. Carr CXCR3 Deficiency Increases Susceptibility to Genital Herpes Simplex Virus Type 2 Infection: Uncoupling of CD8+ T-Cell Effector Function but Not Migration J. Virol., September 15, 2009; 83(18): 9486 - 9501. [Abstract] [Full Text] [PDF]
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