Hepatitis c virus-specific t-cell-derived transforming growth factor beta is associated with slow hepatic fibrogenesis

• Published in: Hepatology (Baltimore, Md.) Vol. 56; no. 6; pp. 2094 - 2105
• Main Authors: Li, Shaoyong, Vriend, Lianne E.M., Nasser, Imad A., Popov, Yury, Afdhal, Nezam H., Koziel, Margaret J., Schuppan, Detlef, Exley, Mark A., Alatrakchi, Nadia
• Format: Journal Article
• Language: English
• Published: Hoboken Wiley Subscription Services, Inc., A Wiley Company 01.12.2012; Wiley; Wolters Kluwer Health, Inc
• Subjects: Adult; Aged; Biological and medical sciences; CD8-Positive T-Lymphocytes - immunology; CD8-Positive T-Lymphocytes - metabolism; Collagen Type I - genetics; Cross-Sectional Studies; Cytokines; Disease Progression; Female; Gastroenterology. Liver. Pancreas. Abdomen; Gene Expression; Hepacivirus - immunology; Hepatic Stellate Cells - metabolism; Hepatitis; Hepatitis C; Hepatitis C, Chronic - immunology; Hepatitis C, Chronic - metabolism; Hepatitis C, Chronic - pathology; Hepatology; Humans; Interferon-gamma - metabolism; Interleukin-10 - metabolism; Liver - immunology; Liver - metabolism; Liver cirrhosis; Liver Cirrhosis - immunology; Liver Cirrhosis - metabolism; Liver Cirrhosis - pathology; Liver. Biliary tract. Portal circulation. Exocrine pancreas; Lymphocytes; Male; Matrix Metalloproteinase 1 - genetics; Medical sciences; Middle Aged; T-Lymphocytes, Regulatory - immunology; T-Lymphocytes, Regulatory - metabolism; Transforming Growth Factor beta - metabolism; Viral Core Proteins - immunology; Virus; Cell proliferation; Immunological investigation; Transforming growth factor; Liver; Gastroenterology; T-Lymphocyte; Flaviviridae; Hepatitis C virus; Hepacivirus
• ISSN: 0270-9139; 1527-3350; 1527-3350
• DOI: 10.1002/hep.25951

Hepatitis C virus (HCV)‐specific immune effector responses can cause liver damage in chronic infection. Hepatic stellate cells (HSC) are the main effectors of liver fibrosis. TGFβ, produced by HCV‐specific CD8+ T cells, is a key regulatory cytokine modulating HCV‐specific effector T cells. Here we studied TGFβ as well as other factors produced by HCV‐specific intrahepatic lymphocytes (IHL) and peripheral blood cells in hepatic inflammation and fibrogenesis. This was a cross‐sectional study of two well‐defined groups of HCV‐infected subjects with slow (≤0.1 Metavir units/year, n = 13) or rapid (n = 6) liver fibrosis progression. HCV‐specific T‐cell responses were studied using interferon‐gamma (IFNγ)‐ELISpot ±monoclonal antibodies (mAbs) blocking regulatory cytokines, along with multiplex, enzyme‐linked immunosorbent assay (ELISA) and multiparameter fluorescence‐activated cell sorting (FACS). The effects of IHL stimulated with HCV‐core peptides on HSC expression of profibrotic and fibrolytic genes were determined. Blocking regulatory cytokines significantly raised detection of HCV‐specific effector (IFNγ) responses only in slow fibrosis progressors, both in the periphery (P = 0.003) and liver (P = 0.01). Regulatory cytokine blockade revealed HCV‐specific IFNγ responses strongly correlated with HCV‐specific TGFβ, measured before blockade (R = 0.84, P = 0.0003), with only a trend to correlation with HCV‐specific IL‐10. HCV‐specific TGFβ was produced by CD8 and CD4 T cells. HCV‐specific TGFβ, not interleukin (IL)‐10, inversely correlated with liver inflammation (R = −0.63, P = 0.008) and, unexpectedly, fibrosis (R = −0.46, P = 0.05). In addition, supernatants from HCV‐stimulated IHL of slow progressors specifically increased fibrolytic gene expression in HSC and treatment with anti‐TGFβ mAb abrogated such expression. Conclusion: Although TGFβ is considered a major profibrogenic cytokine, local production of TGFβ by HCV‐specific T cells appeared to have a protective role in HCV‐infected liver, together with other T‐cell‐derived factors, ameliorating HCV liver disease progression. (HEPATOLOGY 2012;56:2094–2105)