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PD-1 inhibits antiviral immunity at the effector phase in the liver.

Iwai Y, Terawaki S, Ikegawa M, Okazaki T, Honjo T - J. Exp. Med. (2003)

Bottom Line: Here we report that PD-L1, the ligand for the immunoinhibitory receptor PD-1, was expressed on vascular endothelium in peripheral tissues.The absence of PD-1 induced proliferation of effector T cells in the adenovirus-infected liver and resulted in rapid clearance of the virus.These results indicate that PD-1 plays an important role in T cell tolerance at the effector phase and the blockade of the PD-1 pathway can augment antiviral immunity.

View Article: PubMed Central - PubMed

Affiliation: Department of Medical Chemistry, Graduate School of Medicine, Kyoto University, Yoshida, Sakyo-ku, Kyoto 606-8501, Japan.

ABSTRACT
Unlike naive T cells, effector T cells can be activated by either T cell receptor signal or costimulatory signal alone and therefore the absence of costimulatory molecules on tissue cells cannot explain the tolerance mechanism at the effector phase. Here we report that PD-L1, the ligand for the immunoinhibitory receptor PD-1, was expressed on vascular endothelium in peripheral tissues. Liver nonparenchymal cells including sinusoidal endothelial cells and Kupffer cells constitutively expressed PD-L1 and inhibited proliferation and cell division of activated T cells expressing PD-1. The absence of PD-1 induced proliferation of effector T cells in the adenovirus-infected liver and resulted in rapid clearance of the virus. These results indicate that PD-1 plays an important role in T cell tolerance at the effector phase and the blockade of the PD-1 pathway can augment antiviral immunity.

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PD-L1 expression on vascular endothelium. (a) ECs were freshly isolated from murine heart and stained with anti-PD-L1 or anti-PD-L2 (open curves). The filled curves represent control IgG. (b-g) Biotinylated F(ab′)2 of anti-PD-L1 (b-g1) or control IgG (b-g2) was intravenously injected into mice and organs were harvested 1 h later. Sections were stained with streptavidin-FITC (green) and counterstained with phalloidin (red). (b) Eye, (c) submandibular gland, (d) lung, (e) heart, (f) liver, (g) kidney. Ch, choroid; CV, central vein; Gl, glomerulus; Re, retina. The arrows represent vascular endothelial cells. Original magnification, ×40.
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fig1: PD-L1 expression on vascular endothelium. (a) ECs were freshly isolated from murine heart and stained with anti-PD-L1 or anti-PD-L2 (open curves). The filled curves represent control IgG. (b-g) Biotinylated F(ab′)2 of anti-PD-L1 (b-g1) or control IgG (b-g2) was intravenously injected into mice and organs were harvested 1 h later. Sections were stained with streptavidin-FITC (green) and counterstained with phalloidin (red). (b) Eye, (c) submandibular gland, (d) lung, (e) heart, (f) liver, (g) kidney. Ch, choroid; CV, central vein; Gl, glomerulus; Re, retina. The arrows represent vascular endothelial cells. Original magnification, ×40.

Mentions: Several studies showed PD-L1 expression on human and murine ECs in culture conditions (20, 40). To determine whether ECs express the PD-L1 protein in vivo, we analyzed freshly isolated ECs from murine heart by flow cytometry using an anti-PD-L1 mAb. The primary EC isolates from heart expressed a low level of PD-L1 but not PD-L2 (Fig. 1 a). To examine PD-L1 distribution in the vascular system in a whole body, we intravenously injected mice with biotinylated F (ab′)2 fragment of anti-PD-L1 mAb or control IgG and examined the antibody staining in tissue sections (Fig. 1, b–g). PD-L1 was found on the vascular endothelium in all tissues examined such as heart, lung, kidney, salivary gland, and eye. In liver, PD-L1 was localized in the hepatic sinusoids. Control IgG had no staining.


PD-1 inhibits antiviral immunity at the effector phase in the liver.

Iwai Y, Terawaki S, Ikegawa M, Okazaki T, Honjo T - J. Exp. Med. (2003)

PD-L1 expression on vascular endothelium. (a) ECs were freshly isolated from murine heart and stained with anti-PD-L1 or anti-PD-L2 (open curves). The filled curves represent control IgG. (b-g) Biotinylated F(ab′)2 of anti-PD-L1 (b-g1) or control IgG (b-g2) was intravenously injected into mice and organs were harvested 1 h later. Sections were stained with streptavidin-FITC (green) and counterstained with phalloidin (red). (b) Eye, (c) submandibular gland, (d) lung, (e) heart, (f) liver, (g) kidney. Ch, choroid; CV, central vein; Gl, glomerulus; Re, retina. The arrows represent vascular endothelial cells. Original magnification, ×40.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2196084&req=5

fig1: PD-L1 expression on vascular endothelium. (a) ECs were freshly isolated from murine heart and stained with anti-PD-L1 or anti-PD-L2 (open curves). The filled curves represent control IgG. (b-g) Biotinylated F(ab′)2 of anti-PD-L1 (b-g1) or control IgG (b-g2) was intravenously injected into mice and organs were harvested 1 h later. Sections were stained with streptavidin-FITC (green) and counterstained with phalloidin (red). (b) Eye, (c) submandibular gland, (d) lung, (e) heart, (f) liver, (g) kidney. Ch, choroid; CV, central vein; Gl, glomerulus; Re, retina. The arrows represent vascular endothelial cells. Original magnification, ×40.
Mentions: Several studies showed PD-L1 expression on human and murine ECs in culture conditions (20, 40). To determine whether ECs express the PD-L1 protein in vivo, we analyzed freshly isolated ECs from murine heart by flow cytometry using an anti-PD-L1 mAb. The primary EC isolates from heart expressed a low level of PD-L1 but not PD-L2 (Fig. 1 a). To examine PD-L1 distribution in the vascular system in a whole body, we intravenously injected mice with biotinylated F (ab′)2 fragment of anti-PD-L1 mAb or control IgG and examined the antibody staining in tissue sections (Fig. 1, b–g). PD-L1 was found on the vascular endothelium in all tissues examined such as heart, lung, kidney, salivary gland, and eye. In liver, PD-L1 was localized in the hepatic sinusoids. Control IgG had no staining.

Bottom Line: Here we report that PD-L1, the ligand for the immunoinhibitory receptor PD-1, was expressed on vascular endothelium in peripheral tissues.The absence of PD-1 induced proliferation of effector T cells in the adenovirus-infected liver and resulted in rapid clearance of the virus.These results indicate that PD-1 plays an important role in T cell tolerance at the effector phase and the blockade of the PD-1 pathway can augment antiviral immunity.

View Article: PubMed Central - PubMed

Affiliation: Department of Medical Chemistry, Graduate School of Medicine, Kyoto University, Yoshida, Sakyo-ku, Kyoto 606-8501, Japan.

ABSTRACT
Unlike naive T cells, effector T cells can be activated by either T cell receptor signal or costimulatory signal alone and therefore the absence of costimulatory molecules on tissue cells cannot explain the tolerance mechanism at the effector phase. Here we report that PD-L1, the ligand for the immunoinhibitory receptor PD-1, was expressed on vascular endothelium in peripheral tissues. Liver nonparenchymal cells including sinusoidal endothelial cells and Kupffer cells constitutively expressed PD-L1 and inhibited proliferation and cell division of activated T cells expressing PD-1. The absence of PD-1 induced proliferation of effector T cells in the adenovirus-infected liver and resulted in rapid clearance of the virus. These results indicate that PD-1 plays an important role in T cell tolerance at the effector phase and the blockade of the PD-1 pathway can augment antiviral immunity.

Show MeSH
Related in: MedlinePlus