Hepatitis B Virus-Specific and Global T-Cell Dysfunction in Chronic Hepatitis B

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• 作者：Jang-June Park¹ ; ² ; David K. Wong³ ; Abdus S. Wahed⁴ ; William M. Lee⁵ ; Jordan J. Feld³ ; Norah Terrault⁶ ; Mandana Khalili⁶ ; Richard K. Sterling⁷ ; Kris V. Kowdley⁸ ; Natalie Bzowej⁹ ; Daryl T. Lau¹⁰ ; W. Ray Kim¹¹ ; Coleman Smith¹² ; Robert L. Carithers¹³ ; Keith W. Torrey¹ ; ² ; James W. Keith¹ ; ² ; Danielle L. Levine¹ ; ² ; Daniel Traum¹ ; ² ; Suzanne Ho¹ ; ² ; Mary E. Valiga¹ ; ² ; Geoffrey S. Johnson⁴ ; Edward Doo¹⁴ ; Anna S.F. Lok¹⁵ ; Kyong-Mi Chang¹ ; ² ; ^{kmchang@mail.med.upenn.edu" class="auth_mail" title="E-mail the corresponding author} ; ^{Kyong-Mi.Chang@va.gov" class="auth_mail" title="E-mail the corresponding author} ; for the Hepatitis B Research NetworkRaymond T. Chung ; MD ; Lewis R. Roberts ; MB ; ChB ; PhD ; Adrian M. Di Bisceglie ; MD ; Mauricio Lisker-Melman ; MD ; Harry L.A. Janssen ; MD ; PhD ; Joshua Juan ; MD ; Colina Yim ; Jenny Heathcote ; MD ; Robert Perrillo ; MD ; Son Do ; MD ; Steven-Huy B. Han ; MD ; Tram T. Tran ; MD ; Stewart L. Cooper ; MD ; Robert J. Fontana ; MD ; Naoky Tsai ; MD ; Michael W. Fried ; MD ; Keyur Patel ; MD ; Donna Evon ; PhD ; Margaret Shuhart ; MD ; Chia C. Wang ; MD ; Marc G. Ghany ; MD ; MHsc ; T. Jake Liang ; MD ; Steven Belle ; PhD ; MScHyg ; Yona Cloonan ; PhD ; David Kleiner ; MD ; PhD
• 关键词：HBRN ; LPS ; IFN ; IL10
• 刊名：Gastroenterology
• 出版年：2016
• 出版时间：March 2016
• 年：2016
• 卷：150
• 期：3
• 页码：684-695.e5
• 全文大小：3051 K

文摘

T cells play a critical role in viral infection. We examined whether T-cell effector and regulatory responses can define clinical stages of chronic hepatitis B (CHB).

Methods

We enrolled 200 adults with CHB who participated in the National Institutes of Health−supported Hepatitis B Research Network from 2011 through 2013 and 20 uninfected individuals (controls). Peripheral blood lymphocytes from these subjects were analyzed for T-cell responses (proliferation and production of interferon gamma and interleukin 10) to overlapping hepatitis B virus (HBV) peptides (preS, S, preC, core, and reverse transcriptase), influenza matrix peptides, and lipopolysaccharide. T-cell expression of regulatory markers FOXP3, programmed death-1, and cytotoxic T lymphocyte-associated antigen-4 was examined by flow cytometry. Immune measures were compared with clinical parameters, including physician-defined immune-active, immune-tolerant, or inactive CHB phenotypes, in a blinded fashion.

Results

Compared with controls, patients with CHB had weak T-cell proliferative, interferon gamma, and interleukin 10 responses to HBV, with increased frequency of circulating FOXP3⁺CD127⁻ regulatory T cells and CD4⁺ T-cell expression of programmed death-1 and cytotoxic T lymphocyte-associated antigen-4. T-cell measures did not clearly distinguish between clinical CHB phenotypes, although the HBV core-specific T-cell response was weaker in hepatitis B e antigen (HBeAg)⁺ than HBeAg⁻ patients (percent responders: 3% vs 23%; P = .00008). Although in vitro blockade of programmed death-1 or cytotoxic T lymphocyte-associated antigen-4 increased T-cell responses to HBV, the effect was weaker in HBeAg⁺ than HBeAg⁻ patients. Furthermore, T-cell responses to influenza and lipopolysaccharide were weaker in CHB patients than controls.

Conclusions

HBV persists with virus-specific and global T-cell dysfunction mediated by multiple regulatory mechanisms, including circulating HBeAg, but without distinct T-cell−based immune signatures for clinical phenotypes. These findings suggest additional T-cell−independent or regulatory mechanisms of CHB pathogenesis that warrant further investigation.