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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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Rapid clearance of adenovirus in the liver of PD-1−/− mice. PD-1−/− or WT mice were intravenously injected with Ad-lacZ. (a–d) At day 0 or day 7 of infection, WT (top) or PD-1−/− mice (bottom) were intraperitoneally injected with BrdU 1 h before killing. Liver sections were stained with anti-BrdU (red). Original magnification, ×20. (e and f) At day 7, liver sections of PD-1−/− mice were doubly stained with anti-BrdU (red), in combination with anti-CD4 (blue, e) or anti-CD8 (blue, f). Original magnification, ×40. (g–r) At day 7 or 30, liver sections of WT mice (top) or PD-1−/− mice (bottom) were analyzed by H&E staining (g–j, ×20; k–n, ×40) and X-Gal staining (×40). The arrows represent apoptotic hepatocytes.
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fig7: Rapid clearance of adenovirus in the liver of PD-1−/− mice. PD-1−/− or WT mice were intravenously injected with Ad-lacZ. (a–d) At day 0 or day 7 of infection, WT (top) or PD-1−/− mice (bottom) were intraperitoneally injected with BrdU 1 h before killing. Liver sections were stained with anti-BrdU (red). Original magnification, ×20. (e and f) At day 7, liver sections of PD-1−/− mice were doubly stained with anti-BrdU (red), in combination with anti-CD4 (blue, e) or anti-CD8 (blue, f). Original magnification, ×40. (g–r) At day 7 or 30, liver sections of WT mice (top) or PD-1−/− mice (bottom) were analyzed by H&E staining (g–j, ×20; k–n, ×40) and X-Gal staining (×40). The arrows represent apoptotic hepatocytes.

Mentions: To investigate the function of PD-1 in liver, we injected PD-1−/− or WT mice intravenously with recombinant lacZ-expressing adenovirus (Ad-lacZ). We compared T cell proliferation in the lymphoid organ (spleen) and inflamed tissue (liver) by in vivo BrdU labeling. At day 0, there were almost no proliferating cells in the liver of both PD-1−/− and WT mice (Fig. 6 a). At day 7, in the infected liver of PD-1−/− mice, infiltrating lymphocytes increased and the percentage of BrdU+CD3+ T cells was much higher than that of WT mice (Fig. 6, b and c). More than 80% of BrdU+ cells composed of CD4 and CD8 T cells in the infected liver of PD-1−/− and WT mice (Fig. 6 b). BrdU+ cells in both CD4 and CD8 T cell populations increased in the liver of PD-1−/− mice as compared with WT mice (Fig. 6, b and c). In contrast, the percentage of BrdU+CD3+ T cells in the spleen of PD-1−/− mice was similar or even less than that of WT mice (Fig. 6, b and c). These results suggest that PD-1 signal inhibits T cell proliferation in inflamed tissues rather than lymphoid organs. Consistent with the FACS analysis, immunohistochemistry showed that BrdU+ cells increased in the infected liver of PD-1−/− mice as compared with WT mice (Fig. 7, a–d). Double staining for BrdU and CD4 or CD8 also confirmed that most of BrdU+ cells were CD4 or CD8 T cells (Fig. 6 b, and Fig. 7, e and f).


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)

Rapid clearance of adenovirus in the liver of PD-1−/− mice. PD-1−/− or WT mice were intravenously injected with Ad-lacZ. (a–d) At day 0 or day 7 of infection, WT (top) or PD-1−/− mice (bottom) were intraperitoneally injected with BrdU 1 h before killing. Liver sections were stained with anti-BrdU (red). Original magnification, ×20. (e and f) At day 7, liver sections of PD-1−/− mice were doubly stained with anti-BrdU (red), in combination with anti-CD4 (blue, e) or anti-CD8 (blue, f). Original magnification, ×40. (g–r) At day 7 or 30, liver sections of WT mice (top) or PD-1−/− mice (bottom) were analyzed by H&E staining (g–j, ×20; k–n, ×40) and X-Gal staining (×40). The arrows represent apoptotic hepatocytes.
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fig7: Rapid clearance of adenovirus in the liver of PD-1−/− mice. PD-1−/− or WT mice were intravenously injected with Ad-lacZ. (a–d) At day 0 or day 7 of infection, WT (top) or PD-1−/− mice (bottom) were intraperitoneally injected with BrdU 1 h before killing. Liver sections were stained with anti-BrdU (red). Original magnification, ×20. (e and f) At day 7, liver sections of PD-1−/− mice were doubly stained with anti-BrdU (red), in combination with anti-CD4 (blue, e) or anti-CD8 (blue, f). Original magnification, ×40. (g–r) At day 7 or 30, liver sections of WT mice (top) or PD-1−/− mice (bottom) were analyzed by H&E staining (g–j, ×20; k–n, ×40) and X-Gal staining (×40). The arrows represent apoptotic hepatocytes.
Mentions: To investigate the function of PD-1 in liver, we injected PD-1−/− or WT mice intravenously with recombinant lacZ-expressing adenovirus (Ad-lacZ). We compared T cell proliferation in the lymphoid organ (spleen) and inflamed tissue (liver) by in vivo BrdU labeling. At day 0, there were almost no proliferating cells in the liver of both PD-1−/− and WT mice (Fig. 6 a). At day 7, in the infected liver of PD-1−/− mice, infiltrating lymphocytes increased and the percentage of BrdU+CD3+ T cells was much higher than that of WT mice (Fig. 6, b and c). More than 80% of BrdU+ cells composed of CD4 and CD8 T cells in the infected liver of PD-1−/− and WT mice (Fig. 6 b). BrdU+ cells in both CD4 and CD8 T cell populations increased in the liver of PD-1−/− mice as compared with WT mice (Fig. 6, b and c). In contrast, the percentage of BrdU+CD3+ T cells in the spleen of PD-1−/− mice was similar or even less than that of WT mice (Fig. 6, b and c). These results suggest that PD-1 signal inhibits T cell proliferation in inflamed tissues rather than lymphoid organs. Consistent with the FACS analysis, immunohistochemistry showed that BrdU+ cells increased in the infected liver of PD-1−/− mice as compared with WT mice (Fig. 7, a–d). Double staining for BrdU and CD4 or CD8 also confirmed that most of BrdU+ cells were CD4 or CD8 T cells (Fig. 6 b, and Fig. 7, e and f).

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