Dissection of a Circulating and Intrahepatic CD4⁺ Foxp3⁺ T-Cell Subpopulation in Chronic Hepatitis B Virus (HBV) Infection: A Highly Informative Strategy for Distinguishing Chronic HBV Infection States

• Published in: The Journal of infectious diseases Vol. 205; no. 7; pp. 1111 - 1120
• Main Authors: Zhang, Mengjun, Zhou, Jijun, Zhao, Tingting, Huang, Guangyu, Tan, Yulong, Tan, Shun, Fu, Xiaolan, Niu, Wei, Meng, Gang, Chen, Xiaoling, Shang, Xiaoyun, Liu, Dong, Ni, Bing, Wang, Li, Wu, Yuzhang
• Format: Journal Article
• Language: English
• Published: Oxford Oxford University Press 01.04.2012
• Subjects: Antigens; Biological and medical sciences; CD4-Positive T-Lymphocytes - chemistry; CD4-Positive T-Lymphocytes - immunology; Chronic hepatitis; DNA damage; DNA, Viral - blood; Flow Cytometry; Forkhead Transcription Factors - analysis; Fundamental and applied biological sciences. Psychology; Hepatitis; Hepatitis B Core Antigens - immunology; Hepatitis B virus; Hepatitis B virus - immunology; Hepatitis B virus - isolation & purification; Hepatitis B, Chronic - immunology; Hepatitis B, Chronic - pathology; Human viral diseases; Humans; Infections; Infectious diseases; Interleukins; Liver; Lymphocyte Subsets - chemistry; Lymphocyte Subsets - immunology; Medical sciences; Microbiology; Miscellaneous; T lymphocytes; T-Lymphocytes, Regulatory - chemistry; T-Lymphocytes, Regulatory - immunology; Viral diseases; Viral hepatitis; Viral Load; Viremia; Virology; Viruses; Orthohepadnavirus; Hepatic disease; Cell subpopulation; Virus; Viral hepatitis B; Infection; Viral hepatitis A; Chronic; Hepadnaviridae; Viral disease; T-Lymphocyte; Digestive diseases; Hepatitis B virus
• ISSN: 0022-1899; 1537-6613
• DOI: 10.1093/infdis/jis011

Background. The definition of CD4⁺ Foxp3⁺ regulatory T cells (Tregs) is challenging as it relates to chronic hepatitis B virus (HBV) infection. Recently, the heterogeneity of human CD4⁺ Foxp3⁺ T cells has been confirmed. Methods. Three circulating CD4⁺ Foxp3⁺ T-cell subpopulations in chronic HBV patients were identified, and their frequencies associated with clinical parameters were analyzed. Antigen specificity of Tregs was further studied. Results. We found that circulating and intrahepatic CD4⁺ CD45RA Foxp3 hl -activated Tregs (aTregs) were selectively increased in patients with chronic active hepatitis  and acute-on-chronic liver failure (ACLF) but not in asymptomatic carriers. The aTreg frequency was strongly correlated with HBV DNA load but not liver damage. In both peripheral blood mononuclear cells and livers, ACLF patients showed a dramatically elevated frequency of interleukin 17A-secreting CD45RA~ Foxp3 l0 nonsuppressive Ô cells (non-Tregs), which were shown to be associated with severe liver damage. Interestingly, an HBV core antigen (HBcAg)-derived peptide could preferentially expand CD4 ⁺ CD25 ⁺ Foxp3 ⁺ Ô cells and aTregs in HLA-DR9 ⁺ chronic active hepatitis  patients, and these Tregs required ligand-specific reactivation for suppressor function. Conclusions. The delineation of a CD4⁺ Foxp3⁺ T-cell subpopulation is a highly informative strategy for distinguishing different chronic HBV infection states. HBcAg-derived peptides may be responsible for activation of Tregs that, in turn, specifically inhibit anti-HBV immune response but not liver inflammation.