Restoration of type I interferon signaling in intrahepatically primed CD8+ T cells promotes functional differentiation

Kawashima, Keigo; Isogawa, Masanori; Onishi, Mai; Baudi, Ian; Saito, Satoru; Nakajima, Atsushi; Fujita, Takashi; Tanaka, Yasuhito

doi:10.1172/jci.insight.145761

Cited by 8 publications

(6 citation statements)

References 40 publications

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“…Poignancy induction of type I interferon (IFN-Is) in the liver also promoted the functional differentiation of intrahepatic perfusion of HBV-specific CD8 + T cells while restoring ISGs expression in T cells, suggesting that robust induction of intrahepatic IFN-Is may be therapeutic for CHB. 20 Prospective studies confirmed that increased frequency of HBV-specific functional CD8 + T cells in NAs discontinuation patients was associated with continued viral control after treatment. Although HBV-specific CD4 + T-cell response is observed with a similar trend, without statistical significance.…”

Section: Virus -S Pecific Cd8 + T Cell S During Hbv Infec Ti Onmentioning

confidence: 88%

“…Moreover, the expression of interferon stimulator genes (ISGs) was reported to be associated with selective inhibition of some special functions of CD8 + T cells. Poignancy induction of type I interferon (IFN‐Is) in the liver also promoted the functional differentiation of intrahepatic perfusion of HBV‐specific CD8 + T cells while restoring ISGs expression in T cells, suggesting that robust induction of intrahepatic IFN‐Is may be therapeutic for CHB 20 . Prospective studies confirmed that increased frequency of HBV‐specific functional CD8 + T cells in NAs discontinuation patients was associated with continued viral control after treatment.…”

Section: Virus‐specific Cd8+ T Cells During Hbv Infectionmentioning

confidence: 99%

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Role of CXCR5⁺CD8⁺ T cells in human hepatitis B virus infection

Zhou

et al. 2023

Journal of Viral Hepatitis

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Human hepatitis B virus (HBV) infection, a primary cause of cirrhosis and liver cancer worldwide, remains a global public health concern due to the associated high morbidity and mortality rates. 1,2 Generally, HBV infection can be controlled by reverse-transcriptase inhibitors (nucleos (t) ide analogs [NAs]) and interferon (IFN) therapy. However, both these medications are available in limited quantities for eliminating HBV. Although antiviral therapy can efficaciously inhibit viral replication and significantly delay disease progression in patients infected with HBV, it is not curative and must be taken for a long period or even a lifetime. 3 Furthermore, once antiviral therapy is discontinued, new intact virus particles can be resynthesized, resulting from the covalently closed circular DNA (cccDNA). 4 Another major cause of the long-term existence of HBV is the dysfunction of the adaptive immune response, and the principal mechanism at play here is the immune tolerance induced by multiple viral antigens (e.g. HBV surface antigen, e antigen, core antigen). 5 Consequently,

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Section: Virus -S Pecific Cd8 + T Cell S During Hbv Infec Ti Onmentioning

confidence: 88%

Section: Virus‐specific Cd8+ T Cells During Hbv Infectionmentioning

confidence: 99%

Role of CXCR5⁺CD8⁺ T cells in human hepatitis B virus infection

Zhou

et al. 2023

Journal of Viral Hepatitis

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“…In stark contrast to exhausted CD8+ T cells during LCMV infection, genes related to IFN-I signaling activation were downregulated in intrahepatically primed T cells. Importantly, strong stimulation of IFN-I signaling in the liver enhanced T cell responses (82), suggesting that IFN-Is indeed provide the third signal (signal 3) that complements the TCR signal (signal 1) and co-stimulatory signal (signal 2). It should be noted, however, that the same IFN-I signaling could suppress HBV-specific CD8+ T cell responses by reducing antigen expression levels during the early phase of T cell priming (67), a phenomenon recently highlighted in the development of RNA vaccines (83).…”

Section: Intrahepatic Antigen Recognitionmentioning

confidence: 99%

HBV-Specific CD8+ T-Cell Tolerance in the Liver

2021

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Hepatitis B virus (HBV) remains a leading cause of liver-related morbidity and mortality through chronic hepatitis that may progress to liver cirrhosis and cancer. The central role played by HBV-specific CD8+ T cells in the clearance of acute HBV infection, and HBV-related liver injury is now well established. Vigorous, multifunctional CD8+ T cell responses are usually induced in most adult-onset HBV infections, while chronic hepatitis B (CHB) is characterized by quantitatively and qualitatively weak HBV-specific CD8+ T cell responses. The molecular basis of this dichotomy is poorly understood. Genomic analysis of dysfunctional HBV-specific CD8+ T cells in CHB patients and various mouse models suggest that multifaceted mechanisms including negative signaling and metabolic abnormalities cooperatively establish CD8+ T cell dysfunction. Immunoregulatory cell populations in the liver, including liver resident dendritic cells (DCs), hepatic stellate cells (HSCs), myeloid-derived suppressor cells (MDSCs), may contribute to intrahepatic CD8+ T cell dysfunction through the production of soluble mediators, such as arginase, indoleamine 2,3-dioxygenase (IDO) and suppressive cytokines and the expression of co-inhibitory molecules. A series of recent studies with mouse models of HBV infection suggest that genetic and epigenetic changes in dysfunctional CD8+ T cells are the manifestation of prolonged antigenic stimulation, as well as the absence of co-stimulatory or cytokine signaling. These new findings may provide potential new targets for immunotherapy aiming at invigorating HBV-specific CD8+ T cells, which hopefully cures CHB.

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“…Because HBcAg cannot be secreted into circulation, these findings again clearly indicate that expression of viral antigen in hepatocytes is tolerogenic due to the lack of sufficient costimulatory signals and reduction of HBcAg expression in hepatocytes by more than 10 folds cannot prevent the induction of CD8+ T cell tolerance. However, it was found that treatment of HBV transgenic mice with type I IFN or IL-2 can rescue, at least in part, the development of the adoptively transferred HBV-specific naïve CD8+ T cells to functional effectors CTLs (50,55). These findings imply that IFN-α or pattern recognition receptor (PRR) agonist therapy of CHB may activate host antiviral immune response via partially rescuing the functional development of hepatocyte-primed CTLs (Fig.…”

Section: Effects Of Reducing Intrahepatic Viral Protein Expression And/or Circulating Hbsag On Antiviral Immune Responses In Mouse Modelsmentioning

confidence: 99%

Restoration of a functional antiviral immune response to chronic HBV infection by reducing viral antigen load: if not sufficient, is it necessary?

Yang

Zeng

Zhang

et al. 2021

Emerging Microbes & Infections

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The prolonged viral antigen stimulation is the driving force for the development of immune tolerance to chronic hepatitis B virus (HBV) infection. The sustained reduction of viral proteins may allow for the recovery and efficient activation of HBV-specific T and B cells by immune stimulating agents, checkpoint blockades and/or therapeutic vaccinations. Recently, several therapeutic approaches have been shown to significantly reduce intrahepatic viral proteins and/or circulating HBV surface antigen (HBsAg) with variable impacts on the host antiviral immune responses in animal models or human clinical trials. It remains to be further investigated whether reduction of viral protein expression or induction of intrahepatic viral protein degradation is more efficacious to break the immune tolerance to chronic HBV infection. It is also of great interest to know if the accelerated clearance of circulating HBsAg by antibodies has a long term immunological impact on HBV infection and disease progression. Although it is clear that removal of antigen stimulation alone is not sufficient to induce the functional recovery of exhausted T and B cells, accumulating evidence suggests that the reduction of viral antigen load appears to facilitate the therapeutic activation of a functional antiviral immunity in chronic HBV carriers. Based on systematic review of the findings in animal models and clinical studies, the research directions toward discovery and development of more efficacious therapeutic approaches to reinvigorate HBV-specific adaptive immune function and achieve the durable control of chronic HBV infection, i.e., a functional cure, in the vast majority of treated patients are discussed.

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Restoration of type I interferon signaling in intrahepatically primed CD8+ T cells promotes functional differentiation

Cited by 8 publications

References 40 publications

Role of CXCR5⁺CD8⁺ T cells in human hepatitis B virus infection

Role of CXCR5⁺CD8⁺ T cells in human hepatitis B virus infection

HBV-Specific CD8+ T-Cell Tolerance in the Liver

Restoration of a functional antiviral immune response to chronic HBV infection by reducing viral antigen load: if not sufficient, is it necessary?

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Restoration of type I interferon signaling in intrahepatically primed CD8+ T cells promotes functional differentiation

Cited by 8 publications

References 40 publications

Role of CXCR5+CD8+ T cells in human hepatitis B virus infection

Role of CXCR5+CD8+ T cells in human hepatitis B virus infection

HBV-Specific CD8+ T-Cell Tolerance in the Liver

Restoration of a functional antiviral immune response to chronic HBV infection by reducing viral antigen load: if not sufficient, is it necessary?

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Product

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Role of CXCR5⁺CD8⁺ T cells in human hepatitis B virus infection

Role of CXCR5⁺CD8⁺ T cells in human hepatitis B virus infection