TY - JOUR

T1 - Binding of the placental growth factor to VEGF receptor type 1 modulates human T cell functions

AU - Leplina, Olga

AU - Smetanenko, Ekaterina

AU - Tikhonova, Marina

AU - Batorov, Egor

AU - Tyrinova, Tamara

AU - Pasman, Natalya

AU - Ostanin, Alexander

AU - Chernykh, Elena

N1 - ©2020 Society for Leukocyte Biology.

PY - 2020/9/1

Y1 - 2020/9/1

N2 - 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 (3H-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.

AB - 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 (3H-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.

KW - apoptosis

KW - CTLA-4

KW - IL-10

KW - PD-1

KW - PlGF

KW - TIM-3

KW - Т cells

KW - PD-1/PD-L1 PATHWAY

KW - OVARIAN-CANCER

KW - INTERLEUKIN-10

KW - T cells

KW - PREGNANCY

KW - SIGNAL-TRANSDUCTION

KW - FACTOR PLGF

KW - IMMUNE

KW - DIRECTLY SUPPRESSES ACTIVATION

KW - UP-REGULATION

KW - EXPRESSION

UR - http://www.scopus.com/inward/record.url?scp=85085149165&partnerID=8YFLogxK

U2 - 10.1002/JLB.2A0420-723RR

DO - 10.1002/JLB.2A0420-723RR

M3 - Article

C2 - 32374047

AN - SCOPUS:85085149165

VL - 108

SP - 1013

EP - 1024

JO - Journal of Leukocyte Biology

JF - Journal of Leukocyte Biology

SN - 0741-5400

IS - 3

ER -