Hansenula polymorpha expressed heat shock protein gp96 exerts potent T cell activation activity as an adjuvant

Li, Yang; Song, Haolei; Wang, Yanzhong; Yan, Xiaoli; Bao, Zhao; Zhang, Xiaojun; Wang, Saifeng; Chen, Lizhao; Qiu, Bingsheng; Meng, Songdong

doi:10.1016/j.jbiotec.2010.12.006

Cited by 20 publications

(15 citation statements)

References 33 publications

(47 reference statements)

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“…Female HLA-A2.1/Kb transgenic mice were immunized with HBc DNA-prime/HBc141–149 peptide boost regimen three times, using heat shock protein gp96 as adjuvant (Li et al, 2011). HBc141–149-specific CTL was detected by ELISPOT assay 1 week after the last immunization.…”

Section: Resultsmentioning

confidence: 99%

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A new unconventional HLA-A2-restricted epitope from HBV core protein elicits antiviral cytotoxic T lymphocytes

et al. 2014

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Cytotoxic T cells (CTLs) play a key role in the control of Hepatitis B virus (HBV) infection and viral clearance. However, most of identified CTL epitopes are derived from HBV of genotypes A and D, and few have been defined in virus of genotypes B and C which are more prevalent in Asia. As HBV core protein (HBc) is the most conservative and immunogenic component, in this study we used an overlapping 9-mer peptide pool covering HBc to screen and identify specific CTL epitopes. An unconventional HLA-A2-restricted epitope HBc141–149 was discovered and structurally characterized by crystallization analysis. The immunogenicity and anti-HBV activity were further determined in HBV and HLA-A2 transgenic mice. Finally, we show that mutations in HBc141–149 epitope are associated with viral parameters and disease progression in HBV infected patients. Our data therefore provide insights into the structure characteristics of this unconventional epitope binding to MHC-I molecules, as well as epitope specific CTL activity that orchestrate T cell response and immune evasion in HBV infected patients.

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Section: Resultsmentioning

confidence: 99%

“…with 50 μg of plasmid pcDNA3.1-HBc or pcDNA3.1 (control) at week 1 and subcutaneously with 50 μg of HBc141–149 peptide bound to 30 μg of heat shock protein gp96 as adjuvant (Li et al, 2011) at weeks 3 and 4, respectively. Mice were sacrificed 1 week after the last immunization.…”

Section: Methodsmentioning

confidence: 99%

A new unconventional HLA-A2-restricted epitope from HBV core protein elicits antiviral cytotoxic T lymphocytes

et al. 2014

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“…To study the function of gp96 in the activation of TLRs, we generated a deletion mutant of gp96 lacking its CBD region (gp96-ΔCBD) and introduced Ala substitution mutations at all of the conserved residues in the first half of the CBD (gp96-mut) as shown in Fig 1A . We have shown that eukaryotically expressed recombinant gp96 possesses similar peptide-binding parameters and T cell immune activity as that of native gp96 [ 21 ]. Thus, the wild type and mutant recombinant gp96 proteins were expressed using the baculovirus system.…”

Section: Resultsmentioning

confidence: 99%

“…The substrate TMB (3, 3’, 5, 5’-tetramethylbenzidine) was used for detection. The reaction was measured at 450 nm as described [ 21 ].…”

Section: Methodsmentioning

confidence: 99%

Interaction of Toll-Like Receptors with the Molecular Chaperone Gp96 Is Essential for Its Activation of Cytotoxic T Lymphocyte Response

Liu

Chen

et al. 2016

PLoS ONE

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The heat shock protein gp96 elicits specific T cell responses to its chaperoned peptides against cancer and infectious diseases in both rodent models and clinical trials. Although gp96-induced innate immunity, via a subset of Toll like receptors (TLRs), and adaptive immunity, through antigen presentation, are both believed to be important for priming potent T cell responses, direct evidence for the role of gp96-mediated TLR activation related to its functional T cell activation is lacking. Here, we report that gp96 containing mutations in its TLR-binding domain failed to activate macrophages, but peptide presentation was unaffected. Moreover, we found that peptide-specific T cell responses, as well as antitumor T cell immunity induced by gp96, are severely impaired when the TLR-binding domain is mutated. These data demonstrate the essential role of the gp96-TLR interaction in priming T cell immunity and provide further molecular basis for the coupling of gp96-mediated innate with adaptive immunity.

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“…Mouse immunization. Six-to 8-week-old HLA-A2.1/kb transgenic mice were injected intramuscularly with 50 g of plasmid pcDNA-HBcP130 or pcDNA-HBc-T130 at week 1 and subcutaneously with 50 g of peptides bound to 30 g of recombinant heat shock protein gp96 (35,36) at weeks 3 and 4, respectively. Mice were sacrificed at week 5, and splenocytes were isolated as previously described (37).…”

Section: Methodsmentioning

confidence: 99%

CD8 ⁺ T-Cell Response-Associated Evolution of Hepatitis B Virus Core Protein and Disease Progress

Deng

et al. 2018

J Virol

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Under the immune pressure of cytotoxic T cells (CTLs), hepatitis B virus (HBV) evolves to accumulate mutations more likely within epitopes to evade immune detection. However, little is known about the specific patterns of the immune pressure-associated HBV mutation of T-cell epitopes and their link to disease progression. Here, we observed a correlation of the accumulated variants on HBV core protein (HBc) with the disease severity of HBV infection. Further analysis indicated that these substitutions were mostly located within CD8 T-cell epitopes of HBc protein, which were systematically screened and identified in an unbiased manner in our study. From individual peptide level to the human leukocyte antigen I (HLA-I)-restricted population level, we elucidated that the mutations in these well-defined HLA-I-restricted T-cell epitopes significantly decreased antiviral activity-specific CTLs and were positively associated with clinical parameters and disease progression in HBV-infected patients. The molecular pattern for viral epitope variations based on the sequencing of 105 HBV virus genomes indicated that the C-terminal portion (Pc), especially the Pc-1 and Pc-2 positions, have the highest mutation rates. Further structural analysis of HLA-A*02 complexed to diverse CD8 T-cell epitopes revealed that the highly variable C-terminal bulged peak of M-shaped HBc-derived epitopes are solvent exposed, and most of the CDR3βs of the T-cell receptor hover over them. These data shed light on the molecular and immunological mechanisms of T-cell immunity-associated viral evolution in hepatitis B progression, which is beneficial for designing immunotherapies and vaccines. The specific patterns of sequence polymorphisms of T-cell epitopes and the immune mechanisms of the HBV epitope mutation-linked disease progression are largely unclear. In this study, we systematically evaluated the contribution of CD8 T cells to the disease progress-associated evolution of HBV. By evaluation of patient T-cell responses based on the peptide repertoire, we comprehensively characterized the association of clinical parameters in chronic hepatitis B with the antiviral T-cell response-associated mutations of the viruses from the single-epitope level to the overall HLA-I-restricted peptide levels. Furthermore, we investigated the molecular basis of the HLA-A2-restricted peptide immune escape and found that the solvent-exposed C-terminal portion of the epitopes is highly variable under CDR3β recognition. Our work may provide a comprehensive evaluation of viral mutations impacted by the host CTL response in HBV disease progression in the context of the full repertoire of HBc-derived epitopes.

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Hansenula polymorpha expressed heat shock protein gp96 exerts potent T cell activation activity as an adjuvant

Cited by 20 publications

References 33 publications

A new unconventional HLA-A2-restricted epitope from HBV core protein elicits antiviral cytotoxic T lymphocytes

A new unconventional HLA-A2-restricted epitope from HBV core protein elicits antiviral cytotoxic T lymphocytes

Interaction of Toll-Like Receptors with the Molecular Chaperone Gp96 Is Essential for Its Activation of Cytotoxic T Lymphocyte Response

CD8 ⁺ T-Cell Response-Associated Evolution of Hepatitis B Virus Core Protein and Disease Progress

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Hansenula polymorpha expressed heat shock protein gp96 exerts potent T cell activation activity as an adjuvant

Cited by 20 publications

References 33 publications

A new unconventional HLA-A2-restricted epitope from HBV core protein elicits antiviral cytotoxic T lymphocytes

A new unconventional HLA-A2-restricted epitope from HBV core protein elicits antiviral cytotoxic T lymphocytes

Interaction of Toll-Like Receptors with the Molecular Chaperone Gp96 Is Essential for Its Activation of Cytotoxic T Lymphocyte Response

CD8 + T-Cell Response-Associated Evolution of Hepatitis B Virus Core Protein and Disease Progress

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CD8 ⁺ T-Cell Response-Associated Evolution of Hepatitis B Virus Core Protein and Disease Progress