Detection of Functionally Altered Hepatitis C Virus–Specific Cd4+ T Cells in Acute and Chronic Hepatitis C

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Abstract
Chronic hepatitis C is characterized by a weak or absent hepatitis C virus (HCV)–specific CD4+ T–cell response in terms of antigen–specific proliferation or interferon gamma (IFN–γ) secretion. To clarify whether this is due to the absence or functional impairment of antigen–specific CD4+ T cells we developed an assay that relies on the induced expression of the T–cell activation marker CD25 and is therefore independent from cytokine secretion or proliferation. In 10 of 20 patients with chronic hepatitis C, a significant number of antigen–specific activated CD4+ T cells (mean 1.06%/patient; range, 0% to 5.2% of CD4+ T cells) could be shown, whereas antigen–specific proliferation was present in only 1 of 20 patients. IFN–γ secretion was absent in all 13 patients tested. However, significant antigen–specific interleukin 10 (IL–10) and transforming growth factor β (TGF–β) secretion was present in 6 of 10 and 3 of 10 patients, respectively. In 8 patients with acute hepatitis C, irrespective of disease outcome, HCV–specific CD4+ T cells were detected in all patients and at a significantly higher frequency (mean 3.7%/patient; range, 1.16% to 7.17%) in the first weeks of disease. A chronic course of disease was associated either with a loss of both IFN–γ secretion and proliferation, resembling an anergic state, or a loss of T–cell proliferation followed by a rapid decline in IFN–γ–producing cells, corresponding to exhaustion of the specific immune response. In conclusion, functional changes of HCV–specific CD4+ T cells or failure to develop a long–lasting T–helper response may contribute to chronic hepatitis C viral persistence.