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HBcAg-specific CD4+CD25+regulatory T cells modulate immune tolerance and acute exacerbation on the natural history of chronic hepatitis B virus infection

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Journal of Biomedical Science

Summary

Acute exacerbations (AEs) of chronic hepatitis B (CH-B) are accompanied by increased T cell responses to hepatitis B core and e antigens (HBcAg/HBeAg). Why patients are immunotolerant (IT) to the virus and why AEs occur spontaneously on the immunoactive phase remain unclear. The role of HBcAg-specific CD4+CD25+ regulatory T (Treg) cells in AE and IT phases was investigated in this study. The SYFPEITHI scoring system was employed to predict MHC class II-restricted epitope peptides on HBcAg overlap** with HBeAg that were used for Treg-cell cloning and for the construction of MHC class II tetramers to measure Treg cell frequencies (Treg f). The results showed that HBcAg-specific Treg f declined during AE accompanied by increased HBcAg peptide-specific cytotoxic T lymphocyte frequencies. Predominant Foxp3-expressing Treg cell clones were generated from patients on the immune tolerance phase, while the majority of Th1 clones were obtained from patients on the immunoactive phase. Treg cells from liver and peripheral blood of CH-B patients express CD152 and PD1 antigens that exhibit suppression on PBMCs proliferation to HBcAg. These data suggest that HBcAg peptide-specific Treg cells modulate the IT phase, and that their decline may account for the spontaneous AEs on the natural history of chronic hepatitis B virus infection.

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Abbreviations

AE:

acute exacerbation

ALT:

alanine aminotransferase

CH-B:

chronic hepatitis B

CRI-p:

cytotoxicity response index of the peptide

CTLA-4:

cytotoxic T lymphocyte associated antigen-4

ICCS:

intracellular cytokine staining

Foxp3:

forkhead family transcription factor box p3

IT:

immunotolerant

LITs:

liver-infiltrating T lymphocytes

PD1:

program death receptor 1

Th:

T helper cell

Treg :

regulatory T cell

Tcf :

cytotoxic T lymphocyte frequency

Treg f :

Treg cell frequency

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Acknowledgments

The authors are grateful to Miss Chin-Li Lu, statistician, Department of Medical Research, Chi Mei Medical Center for the statistical analysis of data. This work was supported in parts by grants NSC 91-2314-B-384-006-MH, and 94-2314-B-384-013, from the National Science Council, Taipei, Taiwan, and the Chi Mei Foundation CMFHT 9102 and 9401 as well as 94CM-KMU-01, Tainan, Taiwan.

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Authors and Affiliations

  1. Hepatogastroenterology Section, Department of Internal Medicine, Chi Mei Medical Center, Yung-Kang City, Tainan, Taiwan

    I-Che Feng, Lok-Beng Koay, Ming-Jen Sheu, Hsing-Tao Kuo, Chi-Shu Sun & Chuan Lee

  2. Hepatobiliary Division, Kaohsiung Medical University Hospital, Causing, Taiwan

    Wong-Lung Chuang

  3. Graduate Institute of Clinical Medical Sciences, Chang Gung University College of Medicine, Tao Yuen, Taiwan

    Shuen-Kuei Liao

  4. Liver Research Unit, Department of Medical Research, Chi Mei Medical Center, Yung-Kang City, Tainan, Taiwan

    Shih-Ling Wang, Ling-Yu Tang, Chia-Ju Cheng & Sun-Lung Tsai

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  1. I-Che Feng
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Correspondence to Sun-Lung Tsai.

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Feng, IC., Koay, LB., Sheu, MJ. et al. HBcAg-specific CD4+CD25+regulatory T cells modulate immune tolerance and acute exacerbation on the natural history of chronic hepatitis B virus infection. J Biomed Sci 14, 43–57 (2007). https://doi.org/10.1007/s11373-006-9129-z

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