Breakdown of adaptive immunotolerance induces hepatocellular carcinoma in HBsAg-tg mice

Zong, Lu; Peng, Hui; Sun, Cheng; Li, Fenglei; Zheng, Meijuan; Chen, Yongyan; Wei, Haiming; Sun, Rui; Tian, Zhigang

doi:10.1038/s41467-018-08096-8

Cited by 54 publications

(53 citation statements)

References 63 publications

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“…However, immune suppression due to immune checkpoints was also found to enhance viral persistence and lead to chronic infection. The expression levels of PD-1, TIM-3, TIGIT, LAG-3, and CTLA-4 have been observed to increase on peripheral HBV-specific CD8 + T-cells [60][61][62]68,142,143] (Table 2). This upregulation is related to T-cell exhaustion; for example, PD-1/PD-L1 ligation triggers T-cell apoptosis by various mechanisms, potentially assisting with viral persistence in the host [64][65][66].…”

Section: Hepatitis Virus Infection Upregulates Immune Checkpoint Protmentioning

confidence: 98%

Immune Checkpoints in Viral Infections

Cai

Liu

Zhong

et al. 2020

Viruses

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As evidence has mounted that virus-infected cells, such as cancer cells, negatively regulate the function of T-cells via immune checkpoints, it has become increasingly clear that viral infections similarly exploit immune checkpoints as an immune system escape mechanism. Although immune checkpoint therapy has been successfully used in cancer treatment, numerous studies have suggested that such therapy may also be highly relevant for treating viral infection, especially chronic viral infections. However, it has not yet been applied in this manner. Here, we reviewed recent findings regarding immune checkpoints in viral infections, including COVID-19, and discussed the role of immune checkpoints in different viral infections, as well as the potential for applying immune checkpoint blockades as antiviral therapy.

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Section: Hepatitis Virus Infection Upregulates Immune Checkpoint Protmentioning

confidence: 98%

Immune Checkpoints in Viral Infections

Cai

Liu

Zhong

et al. 2020

Viruses

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“…In HBsAg‐transgenic mice (HBs‐tg) model, TIGIT blockade resulted in chronic hepatitis and progression to HCC. HBsAg‐specific T cells emerged following TIGIT blockade, indicating a pivotal role of TIGIT in maintaining immune tolerance to HBsAg in HBs‐tg mice model . Altogether, these data suggest that manipulation of TIGIT pathway is probably valuable for chronic HBV and HCV patients with particular attention to its possible adverse events.…”

Section: The Regulation Of Multiple Ics During Chronic Hbv and Hcv Inmentioning

confidence: 98%

Expressions of inhibitory checkpoint molecules in acute and chronic HBV and HCV infections: Implications for therapeutic monitoring and personalized therapy

Hakim

Rahmadika

Jariah

2019

Reviews in Medical Virology

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Summary The function of T cells is tightly controlled by positive and negative regulations to ensure both successful pathogen elimination and limitation of immune‐mediated pathology. One of the mechanisms to negatively regulate the magnitude and duration of effector T cells is the expression of inhibitory checkpoint molecules (ICs) on the surface membrane of T cells. During acute viral infections, expression of these molecules is upregulated to limit the effector functions following T‐cell activation. The expression is subsequently downregulated following viral clearance. In contrast, these molecules are continuously expressed in virus‐specific T cells found in persistently infected patients, including cases of chronic hepatitis B virus (HBV) and hepatitis C virus (HCV). The continuously high expression of ICs is responsible for the dysfunctional states of HBV‐ and HCV‐specific T cells in chronic phases, known as T‐cell exhaustion. Hence, understanding the regulation of their expression is essential to give insight into pathogenesis as well as the development of effective immune‐based antiviral therapies. This review discusses recent updated research on expression of ICs during acute and chronic phases of HBV and HCV infections as well as during the clinical course of antiviral therapy.

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“…Nevertheless, the resolution of inflammatory processes relies on the tightly controlled balance between pro-inflammatory and regulatory immune responses, which is especially evident during the pathogenesis of neurotropic protozoa such as Plasmodium falciparum, Trypanosoma cruzi, or Toxoplasma gondii, where IL-10 signaling was demonstrated to restrict cytokine-mediated immune pathology 23,24 . TIGIT blockade or deficiency has been shown to lead to the breakdown of peripheral tolerance in HBsAg-tg mice, resulting in the development of hepatitis and fibrosis 25 . At the same time, TIGIT upregulation was shown to support tissue regeneration in vivo by negatively regulating NK cell activation 26 .…”

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confidence: 99%

TIGIT limits immune pathology during viral infections

et al. 2020

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Co-inhibitory pathways have a fundamental function in regulating T cell responses and control the balance between promoting efficient effector functions and restricting immune pathology. The TIGIT pathway has been implicated in promoting T cell dysfunction in chronic viral infection. Importantly, TIGIT signaling is functionally linked to IL-10 expression, which has an effect on both virus control and maintenance of tissue homeostasis. However, whether TIGIT has a function in viral persistence or limiting tissue pathology is unclear. Here we report that TIGIT modulation effectively alters the phenotype and cytokine profile of T cells during influenza and chronic LCMV infection, but does not affect virus control in vivo. Instead, TIGIT has an important effect in limiting immune pathology in peripheral organs by inducing IL-10. Our data therefore identify a function of TIGIT in limiting immune pathology that is independent of viral clearance.

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Breakdown of adaptive immunotolerance induces hepatocellular carcinoma in HBsAg-tg mice

Cited by 54 publications

References 63 publications

Immune Checkpoints in Viral Infections

Immune Checkpoints in Viral Infections

Expressions of inhibitory checkpoint molecules in acute and chronic HBV and HCV infections: Implications for therapeutic monitoring and personalized therapy

TIGIT limits immune pathology during viral infections

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