Effects of fractalkine on NK cell activity and NK cell-mediated damage of endothelial cells

Abstract

Chemokines were initially reported as chemoattractant cytokines synthesized at inflammation sites and have been shown to induce leukocyte activation in various diseases, including autoimmune diseases, and in graft rejection sites. Natural killer (NK) cells, which express cytolytic activity without prior antigenic stimulation, are involved in the therateutic effect of cancer treated with IL-2 or by adoptive immunotherapy with IL-2. However, both therapies are associated with vascular damage, resulting in a systemic toxicity known as vascular leak syndrome. A novel chemokine, fractalkine, has a unique CX₃C motif and is expressed directly on activated endothelial cells. We investigated the effects of fractalkine on NK cell activity and NK cell-mediated damage of human endothelial cell line ECV 304. Freshly separated NK cells expressed fractalkine receptors and these NK cells efficiently adhered to immobilized fractalkine. lmmobilized fractalkine enhanced NK cell granule exocytosis in a dose-dependent manner. Furthermore, NK cells exhibited increased adherence and enhanced NK cytolytic activity against fractalkine-transfected ECV 304 cells compared to control ECV 304 cells. These results strongly suggest that fractalkine may play an important role not only in the binding of NK cells to endothelial cells, but also in NK cell-mediated endothelial cell damage, leading to vasculopathy and organ failure.