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 approximately 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.
Gasser
Olivier
O
Immunobiology Laboratory, Department of Research, University Hospital, University of Basel, Basel, Switzerland.
Schmid
Thomas A
TA
Zenhaeusern
Gabriela
G
Hess
Christoph
C
D016718:Arachidonic Acid / Q000494:pharmacology; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism / Q000648:ultrastructure*; D002633:Chemotaxis; D003594:Cytoplasmic Granules / Q000737:chemistry*; D005786:Gene Expression Regulation; D006801:Humans; D007249:Inflammation; D011451:Prostaglandin-Endoperoxide Synthases / Q000502:physiology*; D054400:Receptors, CCR7; D054367:Receptors, CXCR3; D019707:Receptors, Chemokine / Q000235:genetics*; D023062:Receptors, Interleukin-8A / Q000235:genetics*
C515370:CCR7 protein, human; C515187:CXCR3 protein, human; D054400:Receptors, CCR7; D054367:Receptors, CXCR3; D019707:Receptors, Chemokine; D023062:Receptors, Interleukin-8A; D016718:Arachidonic Acid; D011451:Prostaglandin-Endoperoxide Synthases