PD-L1 is induced in hepatocytes by viral infection and by interferon-α and -γ and mediates T cell apoptosis

Mechanisms contributing to the development of chronic viral infections, including chronic hepatitis B virus (HBV) infections, are not well understood. We have shown recently that production of IFN-γ, an important antiviral cytokine, by HBV-specific CTLs is rapidly induced when they enter the liver of HBV transgenic mice, and then rapidly suppressed, despite the continued presence of Ag. Suppression of IFN-γ production by the CTLs coincides with the up-regulation of programmed cell death (PD)-1, a cell surface signaling molecule known to inhibit T cell function. To determine whether PD-1 plays a role in the functional suppression of IFN-γ secretion by CTLs, we treated HBV transgenic mice with blocking Abs specific for PD ligand (PD-L)1, the most widely expressed PD-1 ligand, and adoptively transferred HBV-specific CTLs. Treatment with anti-PD-L1 Abs resulted in a delay in the suppression of IFN-γ-producing CTLs and a concomitant increase in the absolute number of IFN-γ-producing CTLs in the liver. These results indicate that PD-1:PD-L1 interactions contribute to the suppression of IFN-γ secretion observed following Ag recognition in the liver. Blockade of inhibitory pathways such as PD-1:PD-L1 may reverse viral persistence and chronic infection in cases in which the CTL response is suppressed by this mechanism.

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“…3B). These results are consistent with those recently published regarding expression of PD-L1 on human hepatocytes (38).…”

Section: Ifn-␥ Induces Pd-l1 Expression On Hepatocytessupporting

confidence: 94%

PD-1:PD-L1 Interactions Contribute to the Functional Suppression of Virus-Specific CD8+ T Lymphocytes in the Liver

Maier

Isogawa

Freeman

et al. 2007

The Journal of Immunology

215

172

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“…23,24 Studies in animal models demonstrate that PD-L1 on tumor cells inhibits T-cell activation, decreases T cells' ability to kill tumor cells, and in some cases leads to increased tumor-specific T-cell death. 14,25,26 Indeed, in our experiment, tumor-infiltrating CD8 1 T cells exhibited increased apoptosis induced by anti-CD3. But blocking the PD-1/PD-L1 or PD-1/PD-L2 pathway had little effect on tumor-infiltrating CD8 1 T-cell apoptosis.…”

Section: Discussionsupporting

confidence: 50%

Programmed death-1 upregulation is correlated with dysfunction of tumor-infiltrating CD8+ T lymphocytes in human non-small cell lung cancer

et al. 2010

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T-cell tolerance is an important mechanism for tumor escape, but the molecular pathways involved in T-cell tolerance remain poorly understood. It remains unknown whether the inhibitory immunoreceptor programmed death-1 (PD-1) plays a role in conditions of human non-small cell lung cancer (NSCLC). In this study, we detected PD-1 expression on CD8 1 T cells from healthy control peripheral blood mononuclear cells (PBMCs) and the PBMCs of NSCLC patients as well as NSCLC tissues. Results showed that tumor-infiltrating CD8 1 T cells had increased PD-1 expression and impaired immune function, including reducing cytokine production capability and impairing capacity to proliferate. Blockade of the PD-1/PD-L1 pathway by the PD-L1-specific antibody partially restored cytokine production and cell proliferation. These data provide direct evidence that the PD-1/PD-L1 pathway is involved in CD8 1 T-cell dysfunction in NSCLC patients. Moreover, blocking this pathway provides a potential therapy target in lung cancer.

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“…However as antigen load increases, such as in HIV-1 or HCV, the ability to produce cytokines in response to viral antigens is progressively lost starting with IL-2 then TNF-␣, and finally IFN-␥. 37 Indeed, in our cohort of individuals with chronic HBV infection, we found that both circulating and intrahepatic HBV-specific T cells had low production of IFN-␥, TNF-␣, and even lower IL-2 production. This phenomenon was more evident within the liver, where exposure to antigen was highest.…”

Section: Discussionmentioning

confidence: 61%

“…Recent work has also shown that programmed death ligand-1 expression is upregulated on hepatocytes by both HBV itself and IFN-␥. 37 Programmed death ligand-1 has also been shown to be expressed at high levels in chronic HBV infection. 3 Together with our findings, this suggests that HBV-specific T cells have an "exhausted" phenotype in chronic HBV infection as found in HIV and HCV infection.…”

Section: Discussionmentioning

confidence: 99%

The phenotype of hepatitis B virus-specific T cells differ in the liver and blood in chronic hepatitis B virus infection

et al. 2007

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H epatitis B virus (HBV)-specific T cells are im-portant in the successful clearance of acute HBV infection but also mediate liver damage in both acute and chronic HBV infections. In individuals with chronic HBV infection, circulating HBV-specific T cells are detected infrequently and are significantly reduced compared with individuals who recover from acute HBV infection. [1][2][3] We recently developed a sensitive method to assess HBV-specific T cells using an overlapping peptide library and intracellular cytokine staining (ICS). 4 However, despite detection of interferon-gamma (IFN-␥) HBV-specific T cells in blood, the magnitude of CD4 ϩ and CD8 ϩ HBV-specific T cells in chronic HBV infection was still significantly lower than that observed in other chronic infections such as human immunodeficiency virus (HIV)-1. 3,4 Previous studies using tetramer staining suggested a larger population of HBV-specific T cells being sequestered within the liver than in circulation. 2,5,6 Although a useful tool to quantify virus-specific T cells, the use of tetramers will detect virus-specific T cells regardless of their function or ability to produce cytokine. 7 In addition,

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PD-L1 is induced in hepatocytes by viral infection and by interferon-α and -γ and mediates T cell apoptosis

Cited by 323 publications

References 44 publications

PD-1:PD-L1 Interactions Contribute to the Functional Suppression of Virus-Specific CD8+ T Lymphocytes in the Liver

PD-1:PD-L1 Interactions Contribute to the Functional Suppression of Virus-Specific CD8+ T Lymphocytes in the Liver

Programmed death-1 upregulation is correlated with dysfunction of tumor-infiltrating CD8+ T lymphocytes in human non-small cell lung cancer

The phenotype of hepatitis B virus-specific T cells differ in the liver and blood in chronic hepatitis B virus infection

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