Blocking Chemokine Responsive to γ–2/Interferon (IFN)-γ Inducible Protein and Monokine Induced by IFN-γ Activity In Vivo Reduces the Pathogenetic but not the Antiviral Potential of Hepatitis B Virus–specific Cytotoxic T Lymphocytes

Kakimi, Kazuhiro; Lane, Thomas E.; Wieland, Stefan; Asensio, Valérie C.; Campbell, Iain L.; Chisari, Francis V.; Guidotti, Luca G.

doi:10.1084/jem.194.12.1755

Cited by 223 publications

(202 citation statements)

References 48 publications

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“…4E). This is consistent with previous results from our laboratory showing that secretion of IFN-␥ in the liver by CTLs results in the production of the chemokines IFN-␥-inducible protein-10 (IP-10) and monokine induced by IFN-␥ (MIG) which in turn promote the recruitment of inflammatory cells into the liver (39). sALT activity in PD-L1 mAb-treated mice was also ϳ2-fold higher than untreated controls (Fig.…”

Section: Pd-l1 Blockade Delays Suppression Of Ifn-␥ Production and Insupporting

confidence: 93%

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

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218

172

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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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Section: Pd-l1 Blockade Delays Suppression Of Ifn-␥ Production and Insupporting

confidence: 93%

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

Self Cite

218

172

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“…In this setting, NK or resident NK-T cells seem to be the principal source of IFN-␥ production causing rapid inhibition of HBV replication and recruitment of virus-specific and nonspecific cells. 72,86 A similar sequence of events has been reported in patients studied during the incubation phase of hepatitis B. An increased number of circulating NK cells precedes the peak of HBV replication, and is followed, 2 to 4 weeks later, by the appearance of HBV-specific CD8 ϩ T cells, when viral replication has already dropped.…”

Section: The Innate Immune Response In Hcv and Hbv Infectionsmentioning

confidence: 67%

Kinetics of the Immune Response During Hbv and Hcv Infection

2003

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The innate immune system has a role not only in protecting the host during the initial period of virus infection, but also in shaping the nature of the adaptive immune response. In this review, we follow the kinetics of the virologic and immunologic events occurring from the time of hepatitis B virus (HBV) and hepatitis C virus (HCV) infection. We primarily discuss how the early events after infection might influence the development of the adaptive immune response in these 2 important viral infections and how new strategies for more efficient preventive and therapeutic vaccines can be derived from this knowledge. (HEPATOLOGY 2003; 38:4-13.)H epatitis B (HBV) and hepatitis C (HCV) viruses are the 2 major causes of chronic liver inflammation worldwide. 1,2 Despite distinct virologic features, both viruses are preferentially hepatotropic, not directly cytopathic, and elicit liver diseases that share several aspects of their natural history. HBV and HCV infections share also some important features of the adaptive immune response. Multispecific antiviral CD4 and CD8 responses with a T-helper type 1 profile of cytokine production are detectable in the blood of subjects with a self-limited infection. [3][4][5][6][7][8][9][10][11][12][13][14][15][16] These responses are stronger than those found in patients with chronic infection. [17][18][19][20][21] Based on these observations, it has been proposed that the ability to mount an efficient cellular immune response is the main mechanism responsible for HBV and HCV control, whereas a defect in this response leads to chronicity. 2,22 However, the lack of suitable animal models to study the pathogenesis of HBV and HCV infections has so far hampered a definitive demonstration that associations between different infection outcomes and different vigor and breadth of T-cell responses have a causative effect. A recent report in HCV-infected chimpanzees, in which a clear association between T-cell response and virus clearance was not found, 23 added a further note of caution. Even so, it is difficult to argue against the importance of the cellular immune response in HBV and HCV control. In chimpanzees infected with HCV, expansion of a multispecific and sustained HCV-specific CD8 ϩ T-cell-mediated response was observed in 2 of 2 animals that cleared the virus, but not in the 4 animals that developed a chronic infection. 24 These results have been confirmed by recent reports showing that expansion of interferon ␥ (IFN-␥) ϩ , CD8 ϩ , and CD4 ϩ T cells precedes viral clearance in patients studied during the incubation phase of acute HCV infection in man 10 and in HCV-infected chimpanzees. 25 Similar findings have been reported in animal models of HBV infection 26 and in patients studied during the incubation phase of HBV infection, 27 in whom reduced early expansion of virusspecific T cells was associated with virus persistence. Moreover, the importance of virus-specific CD8 ϩ T cells in HBV control has been confirmed further by CD8 ϩ T-cell deletion experiments performed in HBV-i...

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“…Importantly, 84 of these 110 genes were closely correlated with the TCR␤ and -␥ mRNA expression profiles (Table 3), 88 correlated with the induction profiles of MIG, IP-10, or RANTES, which are known to be highly induced by IFN-␥ (21,22), and 79 correlated with sALT levels in all three chimpanzees (Table 3 and Fig. 1).…”

Section: Liver Gene Expression Profiles In Acutely Infectedmentioning

confidence: 86%

Genomic analysis of the host response to hepatitis B virus infection

Wieland

Thimme

Purcell

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

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614

539

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Previous studies in hepatitis B virus (HBV)-infected humans and chimpanzees suggest that control of HBV infection involves the cells, effector functions, and molecular mediators of the immune response. The objective of the current study was to identify, in the liver of acutely HBV-infected chimpanzees, the spectrum of virusinduced and immune response-related genes that regulate the infection. The results demonstrate that HBV does not induce any genes during entry and expansion, suggesting it is a stealth virus early in the infection. In contrast, a large number of T cell-derived IFN-␥-regulated genes are induced in the liver during viral clearance, reflecting the impact of an adaptive T cell response that inhibits viral replication and kills infected cells, thereby terminating the infection.

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Blocking Chemokine Responsive to γ–2/Interferon (IFN)-γ Inducible Protein and Monokine Induced by IFN-γ Activity In Vivo Reduces the Pathogenetic but not the Antiviral Potential of Hepatitis B Virus–specific Cytotoxic T Lymphocytes

Cited by 223 publications

References 48 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

Kinetics of the Immune Response During Hbv and Hcv Infection

Genomic analysis of the host response to hepatitis B virus infection

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