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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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Phenotypic analysis of activated T cells. In vitro–activated CD4+ or CD8+ T cells from PD-1−/− or WT mice were stained with a panel of mAbs (thick lines) and control IgG (thin lines).
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fig3: Phenotypic analysis of activated T cells. In vitro–activated CD4+ or CD8+ T cells from PD-1−/− or WT mice were stained with a panel of mAbs (thick lines) and control IgG (thin lines).

Mentions: In the microanatomical environment of the liver, passenger T cells may be forced to contact with LNPCs in the narrow meshwork of the hepatic sinusoids (26). We assumed that when previously activated T cells pass through liver sinusoids, interaction between PD-1 on activated T cells and PD-L1 on LNPCs might induce suppressive signaling in activated T cells. To examine the function of PD-L1 on LNPCs, in vitro–activated T cells from PD-1−/− or WT mice were cocultured with mitomycin C–treated LNPCs from WT mice to measure T cell proliferation by BrdU incorporation. When naive T cells were stimulated with plate-bound anti-CD3 mAb, both PD-1−/− and WT T cells showed an activated phenotype (CD25high, CD44high, CD69high) (Fig. 3). Activated CD4+ and CD8+ T cells of PD-1−/− and WT mice increased expression levels of PD-L1 and B7–2, but marginally that of B7–1. PD-1 was strongly induced on WT CD4+ and CD8+ T cells. The cell density in the present system appeared to allow T cells to contact with each other and provide costimulatory signal to complement TCR signal by anti-CD3 stimulation. Proliferation of naive PD-1−/− and WT T cells activated with anti-CD3 was comparable (Fig. 4 a).


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)

Phenotypic analysis of activated T cells. In vitro–activated CD4+ or CD8+ T cells from PD-1−/− or WT mice were stained with a panel of mAbs (thick lines) and control IgG (thin lines).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2196084&req=5

fig3: Phenotypic analysis of activated T cells. In vitro–activated CD4+ or CD8+ T cells from PD-1−/− or WT mice were stained with a panel of mAbs (thick lines) and control IgG (thin lines).
Mentions: In the microanatomical environment of the liver, passenger T cells may be forced to contact with LNPCs in the narrow meshwork of the hepatic sinusoids (26). We assumed that when previously activated T cells pass through liver sinusoids, interaction between PD-1 on activated T cells and PD-L1 on LNPCs might induce suppressive signaling in activated T cells. To examine the function of PD-L1 on LNPCs, in vitro–activated T cells from PD-1−/− or WT mice were cocultured with mitomycin C–treated LNPCs from WT mice to measure T cell proliferation by BrdU incorporation. When naive T cells were stimulated with plate-bound anti-CD3 mAb, both PD-1−/− and WT T cells showed an activated phenotype (CD25high, CD44high, CD69high) (Fig. 3). Activated CD4+ and CD8+ T cells of PD-1−/− and WT mice increased expression levels of PD-L1 and B7–2, but marginally that of B7–1. PD-1 was strongly induced on WT CD4+ and CD8+ T cells. The cell density in the present system appeared to allow T cells to contact with each other and provide costimulatory signal to complement TCR signal by anti-CD3 stimulation. Proliferation of naive PD-1−/− and WT T cells activated with anti-CD3 was comparable (Fig. 4 a).

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