Binding of the placental growth factor to VEGF receptor type 1 modulates human T cell functions

The immunosuppressive properties of vascular endothelial growth factors (VEGFs) suggest a new role of angiogenic factors in T cell modulation in cancer and pregnancy. Most of VEGF effects on T cells are mediated through the VEGF receptor type 2 (VEGFR‐2). This study aims to investigate the role of placental growth factor (PlGF) as a selective VEGFR‐1 ligand in the modulation of human T cells functions. For this, PBMCs from healthy donors were stimulated with anti‐CD3 mAbs (a‐CD3) or Concanavalin A (ConA) in the absence or presence of PlGF and assessed for T cell proliferation, IL‐10 production, programmed cell death, and the expression of inhibitory receptors (PD‐1, CTLA‐4, TIM‐3) using radiometric ( 3 H‐thymidine incorporation) and FACS analysis. We showed that most T cells in freshly isolated PBMCs lacked VEGFR‐1. However, activation with a‐CD3 or ConA strongly increased the percentages of VEGFR‐1 expressing CD4 + and CD8 + T cells. PlGF in a wide dose range suppressed PBMC cell proliferation, inhibiting both CD4 + and CD8 + T cells. Blockade of VEGFR‐1, but not VEGFR‐2 with neutralizing Abs completely abolished the suppressive effect of PlGF. Furthermore, we found that treatment with PlGF up‐regulated IL‐10 production in CD4 + and CD8 + T cells, promoted CD8 + T cells apoptosis and enhanced the expression of inhibitory receptors (PD‐1 and TIM‐3) on activated T cells. Our in vitro findings suggest the involvement of PlGF/VEGFR‐1 signaling in the modulation of T cell responses in a‐CD3‐stimulated PBMCs.