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Cyclooxygenase Regulates Cell Surface Expression of CXCR3/1-Storing Granules in Human CD4⁺ T Cells¹

Immunobiology Laboratory, Department of Research, University Hospital Basel, Basel, Switzerland

Efficient migration of CD4⁺ T cells into sites of infection/inflammation is a prerequisite to protective immunity. Inappropriate recruitment, on the other hand, contributes to inflammatory pathologies. The chemokine/chemokine receptor system is thought to orchestrate T cell homing. In this study, we show that most circulating human CD4⁺ T cells store the inflammatory chemokine receptors CXCR3 and CXCR1 within a distinct intracellular compartment. Equipped with such storage granules, CD4⁺ T cells coexpressing both receptors increased from only 1% ex vivo to 30% within minutes of activation with PHA or exposure to the cyclooxygenase (COX) substrate arachidonic acid. Up-regulation was TCR independent and reduced by COX inhibitors at concentrations readily reached in vivo. The inducible inflammatory CXCR3^highCXCR1⁺ phenotype identified nonpolarized cells, was preferentially triggered on CCR7⁺CD4⁺ T cells, and conferred increased chemotactic responsiveness. Thus, inducible CXCR3/1 expression occurs in a large fraction of CD4⁺ T cells. Its dependency on COX may explain a number of established, and point toward novel, effects of COX inhibitors.

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 Swiss Clinicians Opting for Research Grants (3200B0/103253/1 and 3200B0/103254/1) from the Swiss National Science Foundation (to C.H.), the Altana Foundation (to C.H.), the Astra Foundation (to C.H.), and the Novartis Foundation for Medicine and Biology (to O.G. and C.H.).

² Address correspondence and reprint requests to Dr. Christoph Hess, Department of Research, Immunology Laboratory, University of Basel, Switzerland. E-mail address: chess{at}uhbs.ch

³ Abbreviations used in this paper: COX, cyclooxygenase; CytD, cytochalasin D; CHX, cycloheximide; EEA-1, early endosome Ag 1; IP-10, IFN--inducible protein 10.

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