VASCULAR BIOLOGY Effect of vascular endothelial growth factor and its receptor KDR on the transendothelial migration and local trafficking of human T cells in vitro and in vivo

In these studies, we find that the vascular endothelial growth factor (VEGF) receptor KDR is expressed on subsets of mitogenactivated CD4 and CD8 T cells in vitro. We also found that KDR colocalizes with CD3 on mitogen-activated T cells in vitro and on infiltrates within rejecting human allografts in vivo. To evaluate whether VEGF and KDR mediate lymphocyte migration across endothelial cells (ECs), we used an in vitro live-time transmigration model and observed that both anti-VEGF and anti-KDR antibodies inhibit the transmigration of both CD4 and CD8 T cells across tumor necrosis factor (TNF )– activated, but not unactivated ECs. In addition, we found that interactions among CD4 or CD8 T cells and TNF – activated ECs result in the induction of KDR on each T cell subset, and that KDRexpressing lymphocytes preferentially transmigrate across TNF –activated ECs. Finally, using a humanized severe combined immunodeficient mouse model of lymphocyte trafficking, we found that KDRexpressing lymphocytes migrate into human skin in vivo, and that migration is reduced in mice treated with a blocking anti-VEGF antibody. These observations demonstrate that induced expression of KDR on subsets of T cells, and locally expressed VEGF, facilitate ECdependent lymphocyte chemotaxis, and thus, the localization of T cells at sites of inflammation. (Blood. 2010;116(11): 1980-1989)