HCV+ hepatocytes induce human regulatory CD4+ T cells through the production of TGF-beta.
BACKGROUND
Hepatitis C Virus (HCV) is remarkably efficient at establishing persistent infection and is associated with the development of chronic liver disease. Impaired T cell responses facilitate and maintain persistent HCV infection. Importantly, CD4(+) regulatory T cells (Tregs) act by dampening antiviral T cell responses in HCV infection. The mechanism for induction and/or expansion of Tregs in HCV is unknown.


RESULTS
HCV-expressing hepatocytes were used to determine if hepatocytes are able to induce Tregs. The infected liver environment was modeled by establishing the co-culture of the human hepatoma cell line, Huh7.5, containing the full-length genome of HCV genotype 1a (Huh7.5-FL) with activated CD4(+) T cells. The production of IFN-gamma was diminished following co-culture with Huh7.5-FL as compared to controls. Notably, CD4(+) T cells in contact with Huh7.5-FL expressed an increased level of the Treg markers, CD25, Foxp3, CTLA-4 and LAP, and were able to suppress the proliferation of effector T cells. Importantly, HCV(+) hepatocytes upregulated the production of TGF-beta and blockade of TGF-beta abrogated Treg phenotype and function.


CONCLUSIONS
These results demonstrate that HCV infected hepatocytes are capable of directly inducing Tregs development and may contribute to impaired host T cell responses.
Hall
Caroline H T
CH
Department of Microbiology, Beirne B. Carter Center for Immunology Research, University of Virginia, Charlottesville, Virginia, USA.
Kassel
Rachel
R
Tacke
Robert S
RS
Hahn
Young S
YS
D002452:Cell Count; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D015967:Gene Expression Regulation, Viral / Q000276:immunology; D016174:Hepacivirus / Q000235:genetics / Q000502:physiology*; D022781:Hepatocytes / Q000276:immunology* / Q000821:virology*; D006801:Humans; D007371:Interferon-gamma / Q000096:biosynthesis; D010641:Phenotype; D050378:T-Lymphocytes, Regulatory / Q000166:cytology* / Q000378:metabolism* / Q000821:virology; D016212:Transforming Growth Factor beta / Q000096:biosynthesis*; D014764:Viral Proteins / Q000378:metabolism
D016212:Transforming Growth Factor beta; D014764:Viral Proteins; D007371:Interferon-gamma