Cutting Edge: Vascular Endothelial Growth Factor-Mediated Signaling in Human CD45RO+ CD4+ T Cells Promotes Akt and ERK Activation and Costimulates IFN-γ Production

Abstract

In this study, we find that CD45RO+ memory populations of CD4+ T lymphocytes express the vascular endothelial growth factor (VEGF) receptors KDR and Flt-1 at both the mRNA and protein levels. Furthermore, by Western blot analysis, we find that VEGF increases the phosphorylation and activation of ERK and Akt within CD4+CD45RO+ T cells. These VEGF-mediated signaling responses were inhibited by a KDR-specific small interfering RNA in a VEGF receptor-expressing Jurkat T cell line and by SU5416, a pharmacological KDR inhibitor, in CD4+CD45RO+ T cells. We also find that VEGF augments mitogen-induced production of IFN-γ in a dose-dependent manner (p < 0.001) and significantly (p < 0.05) increases directed chemotaxis of this T cell subset. Collectively, our results for the first time define a novel function for VEGF and KDR in CD45RO+ memory T cell responses that are likely of great pathophysiological importance in immunity.

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

“…Chemotaxis assays were also performed across type 1 collagen coated 5M pore polycarbonate filters using the standard Boyden Chamber, according to the manufacturer's instructions (Neuro Probe) as previously described 15 (supplemental Methods).…”

“…13,15,[18][19][20][21] Murine effector T cells express both Flt-1 and KDR, 13 and murine populations of CD4 ϩ CD25 ϩ FoxP3 ϩ T regulatory cells selectively express neuropilin-1. 20,22,23 Human T-cell lines express all VEGF receptors, 15,18,19 and purified subsets of human T cells including CD4 ϩ CD45RO ϩ cells express both Flt-1 and KDR. 15 In addition, KDR, 24,25 like neuropilin-1, 20,26 has been found to be expressed by human FoxP3 ϩ CD4 ϩ T regulatory cells.…”

“…15,31,33 Also, although VEGF receptors have been reported to be expressed by T regulatory cells, 20,[24][25][26] For personal use only. on May 12, 2018. by guest www.bloodjournal.org From VEGF receptor interactions on immunoregulatory cell activity is currently unknown.…”

“…[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.…”

“…20,22,23 Human T-cell lines express all VEGF receptors, 15,18,19 and purified subsets of human T cells including CD4 ϩ CD45RO ϩ cells express both Flt-1 and KDR. 15 In addition, KDR, 24,25 like neuropilin-1, 20,26 has been found to be expressed by human FoxP3 ϩ CD4 ϩ T regulatory cells. Neuropilin-1 has also been reported to be expressed on populations of human naive T cells, where it functions in the initiation of T-cell activation, and in primary immune responses.…”