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

Abstract

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. IntroductionVascular endothelial growth factor (VEGF), an angiogenesis factor, is established to function in the migration, proliferation, and survival of endothelial cells (ECs). 1,2 VEGF is well known to function in wound healing, organ development, and tumor growth and it serves to promote tissue protection and repair after acute injury. 3 VEGF is also expressed in association with cell-mediated immune inflammation and acute and chronic inflammatory reactions. 4 In chronic inflammatory disease processes, VEGF fails to elicit effective tissue repair, and rather may induce a pathologic form of angiogenesis that has been proposed to augment disease activity. 4,5 Indeed, several studies have demonstrated that blockade of VEGF may attenuate the progression of chronic diseases such as arthritis, atherosclerosis, and allograft rejection. [6][7][8] Although relatively underappreciated, VEGF has potent proinflammatory properties including an ability to mediate leukocyte trafficking into sites of cell-mediated immunity. [7][8][9][10][11][12][13] The proinflammatory properties of VEGF are reported to be dependent on its ability to interact directly with monocytes resulting in chemotaxis, 10 its ability to induce the expression of endothelial adhesion molecules 9,11 and chemokine production, 8,12,14 and its ability to enhance vascular permeability. 2 Furthermore, VEGF has been reported to have direct chemoattractant effects on murine and human T cells, 13,15 and blockade of VEGF in vivo has been found to inhibit lymphocyte trafficking into skin and rejecting cardiac allografts. 8,16,17 However, the mechanism underlying the ability of VEGF to interact with T cells is not known, and the molecular basis for its ability to facilitate lymphocyte chemotaxis in vitro or in vivo is poorly understood.Several recent studies have determined that the VEGF receptors Flt-1 (VEGF receptor 1), KDR (VEGF receptor 2) and neu...

DEPTOR regulates vascular endothelial cell activation and proinflammatory and angiogenic responses

“…[1][2][3]38 Activation responses and proinflammatory intracellular signals in ECs are initiated and coordinated by cytokines, 38 growth factors, 2,28 and cell-cell surface receptor-mediated interactions. [38][39][40] In contrast, EC-dependent signals mediating inflammation resolution are poorly defined and less well understood.…”

“…A description of the immunofluorescence technique used in these studies is provided in supplemental Materials and methods, as previously reported. 28 …”

Induction of IL-17 and nonclassical T-cell activation by HIV-Tat protein

“…Ingenuity analysis of the VEGFR2 pathway showed an up-regulation of NME2 and PIM1, VEGFR2 responsive genes, suggesting that VEGFR2 was functionally active (SI Appendix). VEGFR2 is expressed on T cells constitutively at low levels (16,17); however the function of VEGFR2 in lymphocytes is not well understood. To investigate the role of VEGFR2 in Tat induced T-cell activation, T cells were treated with the VEGFR2-specific inhibitor SU1498, which dosedependently inhibited IL-17 production ( Fig.…”

Chronic allograft rejection

“…There is a general consensus that VEGF is a dominant factor mediating vascular remodeling, and it is possible that its expression is a key physiological response to enable repair following acute and chronic injury [38]. However, its newly described effects on the chemotaxis and activation of effector T cells [39-41] and its potential effects on immunoregulatory T cells [42-45] have broad biological and clinical implications for the understanding of chronic rejection.…”