Up-regulation of a death receptor renders antiviral T cells susceptible to NK cell–mediated deletion

Peppa, Dimitra; Gill, Upkar S.; Reynolds, Gary; Easom, Nicholas; Pallett, Laura J.; Schurich, Anna; Micco, L.; Nebbia, Gaia; Singh, Harsimran; Adams, David H.; Kennedy, Patrick T.; Maini, Mala K.

doi:10.1084/jem.20121172

Cited by 301 publications

(290 citation statements)

References 48 publications

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“…Many research groups have shown that NK cells in patients with chronic hepatitis B become defective in terms of producing IFN-c with preserved cytotoxic activity [31][32][33][34][35]. Furthermore, TRAIL (TNF-related apoptosis-inducing ligand)-expressing NK cells eliminate HBV-specific T cells which highly express the TRAIL death receptor TRAIL-R2 [36]. Upon antiviral therapy, IFN-c production by NK cells is partially restored through the downregulation of NKG2A [35].…”

Section: Nk Cells and Dcs In Chronic Hbv Infectionmentioning

confidence: 99%

Host–virus interactions in hepatitis B and hepatitis C infection

Yoshio

Kanto

2016

J Gastroenterol

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Hepatitis B virus (HBV) and hepatitis C virus (HCV) are among the most endemic pathogens worldwide, with more than 500 million people globally currently infected with these viruses. These pathogens can cause acute and chronic hepatitis that progress to liver cirrhosis or hepatocellular carcinoma. Both viruses utilize multifaceted strategies to evade the host surveillance system and fall below the immunological radar. HBV has developed specific strategies to evade recognition by the innate immune system and is acknowledged to be a stealth virus. However, extensive research has revealed that HBV is recognized by dendritic cells (DCs) and natural killer (NK) cells. Indoleamine-2, 3-dioxygenase is an enforcer of sequential immune reactions in acute hepatitis B, and this molecule has been shown to be induced by the interaction of HBV-infected hepatocytes, DCs, and NK cells. The interleukin-28B genotype has been reported to influence HCV eradication either therapeutically or spontaneously, but the biological function of its gene product, a type-III interferon (IFN-k3), remains to be elucidated. Human BDCA3 ? DCs have also been shown to be a potent producer of IFN-k3 in HCV infection, suggesting the possibility that BDCA3 ? DCs could play a key role in developing therapeutic HCV vaccine. Here we review the current state of research on immune responses against HBV and HCV infection, with a specific focus on innate immunity. A comprehensive study based on clinical samples is urgently needed to improve our understanding of the immune mechanisms associated with viral control and thus to develop novel immune modulatory therapies to cure chronic HBV and HCV infection.

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Section: Nk Cells and Dcs In Chronic Hbv Infectionmentioning

confidence: 99%

Host–virus interactions in hepatitis B and hepatitis C infection

Yoshio

Kanto

2016

J Gastroenterol

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“…Some recent studies indicated that NK cells have a suppressive role in anti-viral immunity (e.g., during LCMV and HBV infection). 120,121 NK cells were shown to negatively regulate antiviral immunity in chronic HBV infection by eliminating HBV-specific CD8 1 T cells in a contact-dependent manner by inducing apoptosis. 121 Apoptosis induction by NK cells might be one of the reasons HCC-specific CD8 1 T cells are reduced in HBV-related HCC.…”

Section: Conclusion and Perspectivementioning

confidence: 99%

“…120,121 NK cells were shown to negatively regulate antiviral immunity in chronic HBV infection by eliminating HBV-specific CD8 1 T cells in a contact-dependent manner by inducing apoptosis. 121 Apoptosis induction by NK cells might be one of the reasons HCC-specific CD8 1 T cells are reduced in HBV-related HCC. 122 Further studies are needed to delve into the opposing roles of NK cells in CHB to substantively exploit the potential of NK cells to treat chronic HBV infection and HCC.…”

Section: Conclusion and Perspectivementioning

confidence: 99%

NK cell receptor imbalance and NK cell dysfunction in HBV infection and hepatocellular carcinoma

et al. 2014

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Hepatocellular carcinoma (HCC) is currently the third leading cause of cancer mortality and a common poor-prognosis malignancy due to postoperative recurrence and metastasis. There is a significant correlation between chronic hepatitis B virus (HBV) infection and hepatocarcinogenesis. As the first line of host defense against viral infections and tumors, natural killer (NK) cells express a large number of immune recognition receptors (NK receptors (NKRs)) to recognize ligands on hepatocytes, liver sinusoidal endothelial cells, stellate cells and Kupffer cells, which maintain the balance between immune response and immune tolerance of NK cells. Unfortunately, the percentage and absolute number of liver NK cells decrease significantly during the development and progression of HCC. The abnormal expression of NK cell receptors and dysfunction of liver NK cells contribute to the progression of chronic HBV infection and HCC and are significantly associated with poor prognosis for liver cancer. In this review, we focus on the role of NK cell receptors in anti-tumor immune responses in HCC, particularly HBV-related HCC. We discuss specifically how tumor cells evade attack from NK cells and how emerging understanding of NKRs may aid the development of novel treatments for HCC. Novel mono-and combination therapeutic strategies that target the NK cell receptor-ligand system may potentially lead to successful and effective immunotherapy in HCC. Keywords: activating receptor; hepatocellular carcinoma; inhibitory receptor; natural killer cell; natural killer receptor INTRODUCTION Hepatocellular carcinoma (HCC) is currently the third leading cause of cancer mortality and a common poor-prognosis malignancy due to postoperative recurrence and metastasis. 1 Common clinical risk factors for HCC include hepatitis B virus (HBV)/hepatitis C virus (HCV) infection, heavy alcohol intake, steatohepatitis and diabetes. 2 Approximately 50% of HCC cases worldwide can be attributed to chronic HBV infection (CHB) and almost 75% of HCC cases occur in developing countries where HBV is endemic. 3,4 According to statistics, older male patients who are infected with HBV genotype C or co-infected with HCV, have high levels of viral load and have been exposed to the aflatoxin, or older male patients who have a family history of HCC tend to have a high risk of developing HCC. [5][6][7] Accumulating clinical and epidemiological evidence shows a significant correlation between chronic HBV infection and hepatocarcinogenesis. However, the underlying mechanisms

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“…It has been reported that NK cells regulate T cell responses through multiple direct and indirect mechanisms, including NK cell-mediated killing of activated CD8 + T cells (14,15,(18)(19)(20)(21), CD4 + T cells (18,19,22,23), and also of dendritic cells (DCs) (12,24,25). However, little is known about a possible NK cell-mediated inhibitory/regulatory role during antitumor immune responses.…”

mentioning

confidence: 99%

NK Cells Restrain Spontaneous Antitumor CD8+ T Cell Priming through PD-1/PD-L1 Interactions with Dendritic Cells

Iraolagoitia

Spallanzani

Torres

et al. 2016

The Journal of Immunology

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Despite the classical function of NK cells in the elimination of tumor and of virus-infected cells, evidence for a regulatory role for NK cells has been emerging in different models of autoimmunity, transplantation, and viral infections. However, this role has not been fully explored in the context of a growing tumor. In this article, we show that NK cells can limit spontaneous cross-priming of tumor Ag-specific CD8+ T cells, leading to reduced memory responses. After challenge with MC57 cells transduced to express the model Ag SIY (MC57.SIY), NK cell–depleted mice exhibited a significantly higher frequency of SIY-specific CD8+ T cells, with enhanced IFN-γ production and cytotoxic capability. Depletion of NK cells resulted in a CD8+ T cell population skewed toward an effector memory T phenotype that was associated with enhanced recall responses and delayed tumor growth after a secondary tumor challenge with B16.SIY cells. Dendritic cells (DCs) from NK cell–depleted tumor-bearing mice exhibited a more mature phenotype. Interestingly, tumor-infiltrating and tumor-draining lymph node NK cells displayed an upregulated expression of the inhibitory molecule programmed death ligand 1 that, through interaction with programmed death-1 expressed on DCs, limited DC activation, explaining their reduced ability to induce tumor-specific CD8+ T cell priming. Our results suggest that NK cells can, in certain contexts, have an inhibitory effect on antitumor immunity, a finding with implications for immunotherapy in the clinic.

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Up-regulation of a death receptor renders antiviral T cells susceptible to NK cell–mediated deletion

Abstract: Hepatic NK cells eliminate HBV-specific T cells dependent on TRAIL and TRAIL-R2 interactions to limit antiviral immunity in chronic infection.

Cited by 301 publications

References 48 publications

Host–virus interactions in hepatitis B and hepatitis C infection

Host–virus interactions in hepatitis B and hepatitis C infection

NK cell receptor imbalance and NK cell dysfunction in HBV infection and hepatocellular carcinoma

NK Cells Restrain Spontaneous Antitumor CD8+ T Cell Priming through PD-1/PD-L1 Interactions with Dendritic Cells

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