Hepatitis B and hepatitis C viruses (HBV and HCV) are both noncytopathic and can cause acute and chronic infections of the liver. Although they share tropism for the same organ, development of chronic hepatitis is much more frequent following HCV infection, suggesting different mechanisms of viral persistence. In this study, we show that circulating HBV-and HCV-specific tetramer-positive CD8 cells during the acute phase of hepatitis B and C belong almost entirely to an effector-memory subset (CCR7 ؊ CD45RA ؊ ). Despite this phenotypic similarity, HBV-and HCV-specific CD8 cells show striking functional differences. HBV-specific tetramer-positive CD8 cells express high perforin content ex vivo, expand vigorously, and display efficient cytotoxic activity and gamma interferon (IFN-␥) production upon peptide stimulation. A comparable degree of functional efficiency is maintained after the resolution of hepatitis B. In contrast, HCV-specific CD8 cells in the acute phase of hepatitis C express significantly lower levels of perforin molecules ex vivo and show depressed CD8 function in terms of proliferation, lytic activity, and IFN-␥ production, irrespective of the final outcome of the disease. This defect is transient, because HCV-specific CD8 cells can progressively improve their function in patients with self-limited hepatitis C, while the CD8 function remains persistently depressed in subjects with a chronic evolution.Cytotoxic T lymphocytes (CTL) play a central role in the control of virus infections (15). In infections by noncytopathic viruses, they contribute to both virus elimination and pathology, because elimination of intracellular virus is achieved by the destruction of infected cells and by a cytokine-mediated suppression of viral-gene expression within host cells (6, 11). Therefore, characterization of the functional features of virusspecific CTL at the early stages of infections with noncytopathic viruses, including hepatitis B virus (HBV) and hepatitis C virus (HCV) that are able to chronically persist in the infected host, can provide important insights into the pathogenesis of viral clearance and persistence (4, 7).The use of HLA class I tetramers together with phenotypic markers of activation, homing, and differentiation represents a powerful tool to analyze ex vivo virus-specific CD8 cells (1, 25). Four subsets of CD8 cells can be distinguished by staining them with antibodies to CCR7, a chemokine receptor involved in homing to secondary lymphoid organs and surface molecules associated with naive and memory T-cell subsets: naive CD45RA ϩ CCR7 ϩ T cells, CD45RA Ϫ CCR7 ϩ central memory T cells, CD45RA Ϫ CCR7 Ϫ effector-memory T cells, and CD45RA ϩ CCR7 Ϫ differentiated effector T cells (2, 12, 31). Perforin expression and gamma interferon (IFN-␥) secretion have been reported to be predominant functions of the more differentiated CCR7Ϫ subsets (2, 31). Using tetramer technology to quantify virus-specific CD8 cells, the frequency of tetramer-positive lymphocytes has been shown to be high during the acute...

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Radiofrequency thermal ablation represents an effective treatment for hepatocellular carcinoma (HCC) and it can also exert an "adjuvant" effect on spontaneous antitumor T-cell responses, as suggested by human and animal studies. The adjuvant effect is thought to depend on the huge amount of necrotic tumor antigen made available to the immune system by HCC thermal ablation. In addition, radiofrequency thermal ablation may result in the release of local stimuli responsible for activation and maturation of antigen-presenting cells (APCs). To test this hypothesis, we studied APC maturation and function in 19 patients undergoing thermal ablation for HCC. Patients' monocytes induced to differentiate with granulocyte macrophage colony-stimulating factor (GM-CSF), or GM-CSF plus IL-4, were cocultured in vitro with tumor debris generated by radiofrequency thermal ablation. Expression of costimulatory molecules, lymphnode homing chemokine receptor, antigen presentation, and cytokine secretion were enhanced by incubation with HCC treated tissue as compared with untreated HCC and nontumor liver tissue. Moreover, HCC-specific T-cell responses could be induced by monocytes activated with GM-CSF and incubated with thermally ablated HCC tissue. HCC thermal ablation can create an antigenic source along with stimuli appropriate for maturation of APCs to induce HCC-specific T-cell responses. These results contribute to explain at least in part the adjuvant effect of HCC thermal ablation and suggest a novel strategy to induce maturation of APCs and their loading with HCC antigens for active immunotherapy protocols aimed at reducing HCC recurrence after thermal ablation.

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