Cyclooxygenase regulates cell surface expression of CXCR3/1-storing granules in human CD4+ T cells

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 similar 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(high) CXCR1(+) 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.