Differential presentation of endogenous and exogenous hepatitis B surface antigens influences priming of CD8<sup>+</sup> T cells in an epitope‐specific manner

Riedl, Petra; Reiser, Michael; Stifter, Katja; Krieger, Jana; Schirmbeck, Reinhold

doi:10.1002/eji.201343933

Cited by 7 publications

(16 citation statements)

References 49 publications

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“… 20 , 21 , 22 Similarly, we could induce HBV-C-specific, but not HBV surface-specific, CD8 + T cells in 1.4HBV-S mut tg mice that harbor a replicating HBV genome in hepatocytes by DNA vaccination. 23 , 24 , 25 A single injection of the HBV-C expression vector pCI/C induced K b /C93-specific CD8 + T cells in 1.4HBV-S mut tg mice. Dimer + K b /C93-specific CD8 + T cells accumulated in the liver but were barely detectable in the spleen of 1.4HBV-S mut tg mice.…”

Section: Introductionmentioning

confidence: 99%

“…Dimer + K b /C93-specific CD8 + T cells accumulated in the liver but were barely detectable in the spleen of 1.4HBV-S mut tg mice. 25 K b /C93-specific CD8 + T cells in 1.4HBV-S mut tg mice, but not in B6 mice, largely lost production of interferon (IFN)-γ and upregulated cell surface expression of programmed cell death protein 1 (PD-1), 24 , 25 indicating that they gain an exhausted phenotype. 26 However, the K b /C93-specific CD8 + T cell response in 1.4HBV-S mut tg mice was functional and, at least transiently, inhibited HBV replication in the liver.…”

Section: Introductionmentioning

confidence: 99%

“… 26 However, the K b /C93-specific CD8 + T cell response in 1.4HBV-S mut tg mice was functional and, at least transiently, inhibited HBV replication in the liver. 24 , 25 We thus hypothesized that the binding of cellular RNA to endogenously expressed HBV-C plays a crucial role for priming of antiviral CD8 + T cells in 1.4HBV-S mut tg mice.…”

Section: Introductionmentioning

confidence: 99%

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Endogenously Expressed Antigens Bind Mammalian RNA via Cationic Domains that Enhance Priming of Effector CD8 T Cells by DNA Vaccination

et al. 2019

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Hepatitis B virus (HBV) core (HBV-C) antigens with homologous or heterologous HIV-tat48-57-like (HBV-C149tat) cationic domains non-specifically bind cellular RNA in vector-transfected cells. Here, we investigated whether RNA-binding to cationic domains influences the immunogenicity of endogenously expressed antigens delivered by DNA vaccination. We initially evaluated induction of HBV-C (K b /C93)-specific CD8 + T cell responses in C57BL/6J (B6) and 1.4HBV-S mut transgenic (tg) mice that harbor a replicating HBV genome in hepatocytes by DNA immunization. RNA-binding HBV-C and HBV-C149tat antigens moderately enhanced K b /C93-specific CD8 + T cells in B6 mice as compared with RNA-free HBV-C149 antigen (lacking cationic domains). However, only the RNA-binding antigens elicited K b /C93-specific CD8 + T cells that inhibited HBV replication in 1.4HBV-S mut tg mice. Moreover, RNA-binding to designer antigens, which express a K b /p15E epitope from an endogenous murine leukemia virus-derived tumor-specific gp70 protein, was crucial to prime tumor-rejecting effector CD8 + T cells in B6 mice. Antigen-bound endogenous RNAs function as a Toll-like receptor 7 (TLR-7) ligand and stimulated priming of K b /p15E-specific CD8 + T cells in B6, but not TLR-7 −/− , mice. Antigen-bound cellular RNAs thus function as an endogenous natural adjuvant in in vivo vector-transfected cells, and thus are an attractive tool to induce and/or enhance effector CD8 + T cell responses directed against chronic viral infections or tumor self-antigens by DNA vaccination.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Endogenously Expressed Antigens Bind Mammalian RNA via Cationic Domains that Enhance Priming of Effector CD8 T Cells by DNA Vaccination

et al. 2019

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“…However, endogenously expressed RNA-capturing HBV-C particles also efficiently induced CD8 + T-cell responses and controlled HBV clearance in murine infection model 45 – 47 . Similarly, we could induce HBV-C but not HBV-surface- specific effector CD8 + T-cell responses in 1.4HBV-S mut tg mice that harbor a replicating HBV genome in hepatocytes by DNA-based vaccination 48 – 50 . HBV-C (K b /C93)-specific CD8 + T-cells accumulated in the liver of pCI/C-immune 1.4HBV-S mut tg mice and suppressed (at least transiently) HBV DNA replication 49 , 50 .…”

Section: Discussionmentioning

confidence: 83%

“…Similarly, we could induce HBV-C but not HBV-surface- specific effector CD8 + T-cell responses in 1.4HBV-S mut tg mice that harbor a replicating HBV genome in hepatocytes by DNA-based vaccination 48 – 50 . HBV-C (K b /C93)-specific CD8 + T-cells accumulated in the liver of pCI/C-immune 1.4HBV-S mut tg mice and suppressed (at least transiently) HBV DNA replication 49 , 50 . 1.4HBV-S mut tg mice express endogenous HBV-C and circulating HBV-E antigens in the liver 48 .…”

Section: Discussionmentioning

confidence: 83%

Cationic domains in particle-forming and assembly-deficient HBV core antigens capture mammalian RNA that stimulates Th1-biased antibody responses by DNA vaccination

Krieger

Stifter

Riedl

et al. 2018

Sci Rep

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The HBV core protein self-assembles into particles and encapsidates immune-stimulatory bacterial RNA through a cationic COOH-terminal (C150–183) domain. To investigate if different cationic domains have an impact on the endogenous RNA-binding of HBV-C antigens in mammalian cells, we developed a strep-tag (st) based expression/purification system for HBV-C/RNA antigens in vector-transfected HEK-293 cells. We showed that HBV-stC but not HBV-stC149 particles (lacking the cationic domain) capture low amounts of mammalian RNA. Prevention of specific phosphorylation in cationic domains, either by exchanging the serine residues S155, S162 and S170 with alanines (HBV-stCAAA) or by exchanging the entire cationic domain with a HIV-tat48–57-like sequence (HBV-stC149tat) enhanced the encapsidation of RNA into mutant core particles. Particle-bound mammalian RNA functioned as TLR-7 ligand and induced a Th1-biased humoral immunity in B6 but not in TLR-7−/− mice by exogenous (protein) and endogenous (DNA) vaccines. Compared to core particles, binding of mammalian RNA to freely exposed cationic domains in assembly-deficient antigens was enhanced. However, RNA bound to non-particulate antigens unleash its Th1-stimulating adjuvant activity by DNA- but not protein-based vaccination. Mammalian RNAs targeted by an endogenously expressed antigen thus function as a natural adjuvant in the host that facilitates priming of Th1-biased immune responses by DNA-based immunization.

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Feedback regulation of IFN‐α/β signaling by Axl receptor tyrosine kinase modulates HBV immunity

Huang

Liu

et al. 2015

Eur J Immunol

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Hepatitis B virus (HBV) is known to cause age-dependent infection outcomes wherein most infections during young age result in chronicity.The mechanism underlying the differential outcome remains elusive. By using hydrodynamic injection of the replicationcompetent pAAV-HBV, we established a mouse model in which HBV persistence was generated in 4-5 w/o C57BL/6 young mice, but not in adult mice over 10 w/o. HBV-tolerant young mice expressed higher interferon (IFN)-α/β levels in hepatocytes and intrahepatic plasmacytoid DCs (pDCs) than adult mice after pAAV-HBV injection. Excessive IFN-α/β expression in young mice was associated with induction of the Axl regulatory pathway and expansion of intrahepatic Treg cells. In line with these findings, augmented IFN-β expression increased Axl expression in the liver and HBV persistence in adult mice, whereas IFN-α/β signaling blockage decreased Axl expression and HBV persistence in young mice. Accordingly, Axl overexpression decreased HBV clearance of adult mice whereas Axl silencing enhanced HBV clearance of young mice. In vitro, IFN-β priming of pDCs and Axl-overexpressing macrophages enhanced Treg-cell differentiation. These findings suggest that age-dependent HBV chronicity is attributed to IFN-β-Axl immune regulation, which is selectively induced in young mice by excessive IFN-α/β production at early stage of HBV infection.Keywords: Axl receptor tyrosine kinase r hepatitis B virus (HBV) r immune regulation r TAM receptor tyrosine kinase r type I interferons Additional supporting information may be found in the online version of this article at the publisher's web-site Correspondence: Dr. Miao-Tzu Huang; Dr. Ding-Shinn Chen e-mail: mthuang@ntu.edu.tw; chends@ntu.edu.tw Eur. J. Immunol. 2015Immunol. . 45: 1696Immunol. -1705 Immunity to infection 1697 liver cirrhosis, and hepatocellular carcinoma. In contrast, most HBV infection in the adult often resolves [1,2]. In chronic HBV infection, the host's immune system fails to mount effective anti-HBV immunity [3]. Increased regulatory T (Treg) cells [4] and PD-1-expressing CD8 + T cells [5] have been found in both circulation and livers of the HBV carriers. Neonatal immune responses are characterized by low antibody production, poor cytotoxicity, and Th2-skewed immune responses [6]. Immaturity of the immune system and neonatal tolerance to HBV are currently held responsible for the greatly increased HBV persistence during young age.To this aspect, a recent study has shown that CXCL13, which is involved in B-lymphocyte trafficking and lymphoid development, is expressed in an age-dependent manner in both mouse and human liver macrophages. Therefore, whilst CXCL13 and macrophages facilitate lymphoid organization and successful HBV immunity of the adult, the young mice have abrogated HBV immunity due to greatly diminished CXCL13/macrophage-mediated immune priming [7]. Nonetheless, neonatal immune system is not intrinsically defective and enhanced TLR responses of the neonatal DCs as compared with the adult have been reported [8,9...

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Differential presentation of endogenous and exogenous hepatitis B surface antigens influences priming of CD8⁺ T cells in an epitope‐specific manner

Cited by 7 publications

References 49 publications

Endogenously Expressed Antigens Bind Mammalian RNA via Cationic Domains that Enhance Priming of Effector CD8 T Cells by DNA Vaccination

Endogenously Expressed Antigens Bind Mammalian RNA via Cationic Domains that Enhance Priming of Effector CD8 T Cells by DNA Vaccination

Cationic domains in particle-forming and assembly-deficient HBV core antigens capture mammalian RNA that stimulates Th1-biased antibody responses by DNA vaccination

Feedback regulation of IFN‐α/β signaling by Axl receptor tyrosine kinase modulates HBV immunity

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Differential presentation of endogenous and exogenous hepatitis B surface antigens influences priming of CD8+ T cells in an epitope‐specific manner

Cited by 7 publications

References 49 publications

Endogenously Expressed Antigens Bind Mammalian RNA via Cationic Domains that Enhance Priming of Effector CD8 T Cells by DNA Vaccination

Endogenously Expressed Antigens Bind Mammalian RNA via Cationic Domains that Enhance Priming of Effector CD8 T Cells by DNA Vaccination

Cationic domains in particle-forming and assembly-deficient HBV core antigens capture mammalian RNA that stimulates Th1-biased antibody responses by DNA vaccination

Feedback regulation of IFN‐α/β signaling by Axl receptor tyrosine kinase modulates HBV immunity

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Differential presentation of endogenous and exogenous hepatitis B surface antigens influences priming of CD8⁺ T cells in an epitope‐specific manner