Skewed T-cell receptor beta chain variable gene (TCRBV) usage among different clinical types of patients with chronic HBV infection

Yang, Jiezuan; Chen, Jiajia; Mao, Hejun; Yi, Ping; Dong, Yan; He, Jianqin; Li, Lanjuan

doi:10.1111/j.1574-695x.2012.00969.x

Cited by 13 publications

(10 citation statements)

References 34 publications

(45 reference statements)

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“…These results are consistent with those of other studies suggesting that TCRV β 7 and V β 12 are more abundant than other TCRV β genes in HBV-related infections [19, 40, 45] and other diseases [46]. …”

Section: Discussionsupporting

confidence: 93%

High-Throughput Analysis of the T Cell Receptor Beta Chain Repertoire in PBMCs from Chronic Hepatitis B Patients with HBeAg Seroconversion

Huang

Liu

et al. 2016

Canadian Journal of Infectious Diseases and Medical Microbiolog

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T lymphocytes are the most important immune cells that affect both the development and treatment of hepatitis B. We used high-throughput sequencing to determine the diversity in the V and J regions of the TCRβ chain in 4 chronic hepatitis B patients before and after HBeAg seroconversion. Here, we demonstrate that the 4 patients expressed Vβ12-4 at the highest frequencies of 10.6%, 9.2%, 17.5%, and 7.5%, and Vβ28 was the second most common, with frequencies of 7.8%, 6.7%, 5.3%, and 10.9%, respectively. No significant changes were observed following seroconversion. With regard to the Jβ gene, Jβ2-1 was the most commonly expressed in the 4 patients at frequencies of 5.8%, 6.5%, 11.3%, and 7.3%, respectively. Analysis of the V-J region genes revealed several differences, including significant increases in the expression levels of V7-2-01-J2-1, V12-4-J1-1, and V28-1-J1-5 and a decrease in that of V19-01-J2-3. These results illustrate the presence of biased TCRVβ and Jβ gene expression in the chronic hepatitis B patients. TRBVβ12-4, Vβ28, Jβ2-1, V7-2-01-J2-1, V12-4-J1-1, and V28-1-J1-5 may be associated with the development and treatment of CHB.

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Section: Discussionsupporting

confidence: 93%

High-Throughput Analysis of the T Cell Receptor Beta Chain Repertoire in PBMCs from Chronic Hepatitis B Patients with HBeAg Seroconversion

Huang

Liu

et al. 2016

Canadian Journal of Infectious Diseases and Medical Microbiolog

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“…We hypothesize that aside from epitope-reducing mutations in anchor residues to evade immune detection and destruction, HBV accumulates mutations with immunodominance hierarchy patterns that generate specific CD8 ϩ T cells with relatively low antiviral activity. Indeed, persistent skewed CDR3␤ gene usage was observed in chronic HBV infection, which may be associated with the development and maintenance of hepatitis, pathogenesis, and disease progression (24)(25)(26). This further validates our hypothesis that the high substitution frequency in the solvent-exposed C terminus of the epitopes contributes to immune escape by disrupting T-cell recognition and generating CTL subtypes with low antiviral activity.…”

Section: Discussionsupporting

confidence: 82%

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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“…These studies were carried out usually using the high throughput sequencing (HTS), flow cytometry or molecular cloning techniques. In a previous study, we developed a GMSP assay to determine the clonal expansion status of TCRBV genes in PBMCs, and found that TCRBV11 may be associated with HBV replication in patients with chronic hepatitis B [15,35]. In the present study, the GMSP assay was used to determine the molecular property of skewed TCRBV gene families in PBMCs and CD4 + and CD8 + T cell subsets from active TB and LTBI subjects.…”

Section: Discussionmentioning

confidence: 89%

Molecular characterization of T cell receptor beta variable in the peripheral blood T cell repertoire in subjects with active tuberculosis or latent tuberculosis infection

Yang

Huang

et al. 2013

BMC Infect Dis

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BackgroundT cells are closely linked to the clinical manifestations of subjects with Mycobacterium tuberculosis (MTB) infection. T cell receptor beta variable (TCRBV) is a signal and indicative molecule on the membrane of T lymphocytes, reflecting the composition and specificity of T cells. The molecular profiles of TCRBV in peripheral blood mononuclear cells (PBMCs) and their subpopulations (CD4+ and CD8+ T cells) from subjects with active tuberculosis (TB) or latent TB infection (LTBI) have not been well described.MethodsIn 42 subjects with active TB or LTBI, PMBCs and their subsets were separated and sorted. The molecular profiles of the TCRBV complementarity determining region 3 (CDR3) in the three cell populations were investigated using our recently developed gene melting spectral pattern (GMSP) assay. The TCRBV members were then cloned and sequenced when their GMSP image profiles showed a single-peak.ResultsThe average number of skewed TCRBV molecules in the CD4+ cell subset was significantly higher than that in PBMCs and CD8+ T cells. TCRBV12, BV13.1, BV13.2, and BV24 were expressed more prevalently than other TCRBV gene families in the three cell populations. In addition, relatively conserved amino acid motifs were identified in TCRBV5.1 and BV20 CDR3 in PBMCs and its subsets. The monoclonal TCRBV14 and BV23 expressed were different between active TB and LTBI subjects.ConclusionsThese results indicate that the T cell immune response is complex and multi-specific in active TB and LTBI subjects. Analysis of TCRBV expression in CD4+ T cells suggest that it could be useful in assessing the composition and status of circulating T cells. Furthermore, the expression of TCRBV14, BV23 and the sequencing of CDR3 amino acid motifs of TCRBV5.1, BV20 could be used in the differential diagnosis and treatment of subjects with active TB or LTBI.

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Skewed T-cell receptor beta chain variable gene (TCRBV) usage among different clinical types of patients with chronic HBV infection

Cited by 13 publications

References 34 publications

High-Throughput Analysis of the T Cell Receptor Beta Chain Repertoire in PBMCs from Chronic Hepatitis B Patients with HBeAg Seroconversion

High-Throughput Analysis of the T Cell Receptor Beta Chain Repertoire in PBMCs from Chronic Hepatitis B Patients with HBeAg Seroconversion

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

Molecular characterization of T cell receptor beta variable in the peripheral blood T cell repertoire in subjects with active tuberculosis or latent tuberculosis infection

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Skewed T-cell receptor beta chain variable gene (TCRBV) usage among different clinical types of patients with chronic HBV infection

Cited by 13 publications

References 34 publications

High-Throughput Analysis of the T Cell Receptor Beta Chain Repertoire in PBMCs from Chronic Hepatitis B Patients with HBeAg Seroconversion

High-Throughput Analysis of the T Cell Receptor Beta Chain Repertoire in PBMCs from Chronic Hepatitis B Patients with HBeAg Seroconversion

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

Molecular characterization of T cell receptor beta variable in the peripheral blood T cell repertoire in subjects with active tuberculosis or latent tuberculosis infection

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