Renal tubular PD-L1 (CD274) suppresses alloreactive human T-cell responses

TY - JOUR

T1 - Renal tubular PD-L1 (CD274) suppresses alloreactive human T-cell responses

AU - Starke, Astrid

AU - Lindenmeyer, Maja T

AU - Segerer, Stephan

AU - Neusser, Matthias A

AU - Rüsi, Barbara

AU - Schmid, Daniel M

AU - Cohen, Clemens D

AU - Wüthrich, Rudolf P

AU - Fehr, Thomas

AU - Waeckerle-Men, Ying

PY - 2010/7

Y1 - 2010/7

N2 - Renal proximal tubular epithelial cells, a target of infiltrating T cells during renal allograft rejection, may be protected from this injury by the cell surface protein CD274 (also termed PD-L1 for programmed death ligand 1). The co-inhibitory molecules PD-L1 (CD274) and PD-L2 (CD273) are ligands of PD-1 (programmed death 1; CD279). Here we determine the functional role of PD-1/PD-L pathways in human renal allograft rejection. Treatment of human primary tubular epithelial cells with interferon-beta and -gamma caused a dose-dependent and synergistic increase of PD-L1 and PD-L2 expression. Blockade of surface PD-L1, but not PD-L2, on interferon-treated tubular epithelial cells resulted in a significant increase in CD4+ T-cell proliferation and cytokine production by CD4+ and CD8+ T cells. The expression of PD-L1, PD-L2, and PD-1 mRNA and protein was upregulated in biopsies of patients with renal allograft rejection compared to the respective levels found in the pre-transplant biopsies. Induction of PD-L1 was significantly associated with acute vascular rejection. Our study suggests that the renal epithelial PD-1/PD-L1 pathway exerts an inhibitory effect of on alloreactive T-cell responses. The upregulation of PD-L1 on proximal tubular epithelial cells in patients with acute allograft rejection may reduce T-cell-mediated injury.

AB - Renal proximal tubular epithelial cells, a target of infiltrating T cells during renal allograft rejection, may be protected from this injury by the cell surface protein CD274 (also termed PD-L1 for programmed death ligand 1). The co-inhibitory molecules PD-L1 (CD274) and PD-L2 (CD273) are ligands of PD-1 (programmed death 1; CD279). Here we determine the functional role of PD-1/PD-L pathways in human renal allograft rejection. Treatment of human primary tubular epithelial cells with interferon-beta and -gamma caused a dose-dependent and synergistic increase of PD-L1 and PD-L2 expression. Blockade of surface PD-L1, but not PD-L2, on interferon-treated tubular epithelial cells resulted in a significant increase in CD4+ T-cell proliferation and cytokine production by CD4+ and CD8+ T cells. The expression of PD-L1, PD-L2, and PD-1 mRNA and protein was upregulated in biopsies of patients with renal allograft rejection compared to the respective levels found in the pre-transplant biopsies. Induction of PD-L1 was significantly associated with acute vascular rejection. Our study suggests that the renal epithelial PD-1/PD-L1 pathway exerts an inhibitory effect of on alloreactive T-cell responses. The upregulation of PD-L1 on proximal tubular epithelial cells in patients with acute allograft rejection may reduce T-cell-mediated injury.

KW - Antigens, CD

KW - B7-H1 Antigen

KW - Cell Proliferation

KW - Epithelial Cells

KW - Graft Rejection

KW - Humans

KW - Interferon-beta

KW - Kidney Tubules, Proximal

KW - Ligands

KW - Lymphocyte Activation

KW - Proteins

KW - T-Lymphocytes

KW - Up-Regulation

KW - Journal Article

KW - Research Support, Non-U.S. Gov't

U2 - 10.1038/ki.2010.97

DO - 10.1038/ki.2010.97

M3 - SCORING: Journal article

C2 - 20393451

VL - 78

SP - 38

EP - 47

JO - KIDNEY INT

JF - KIDNEY INT

SN - 0085-2538

IS - 1

ER -