Abnormal Priming of CD4⁺T Cells by Dendritic Cells Expressing Hepatitis C Virus Core and E1 Proteins

Abstract

Patients infected with hepatitis C virus (HCV) have an impaired response against HCV antigens while keeping immune competence for other antigens. We hypothesized that expression of HCV proteins in infected dendritic cells (DC) might impair their antigen-presenting function, leading to a defective anti-HCV T-cell immunity. To test this hypothesis, DC from normal donors were transduced with an adenovirus coding for HCV core and E1 proteins and these cells (DC-CE1) were used to stimulate T lymphocytes. DC-CE1 were poor stimulators of allogeneic reactions and of autologous primary and secondary proliferative responses. Autologous T cells stimulated with DC-CE1 exhibited a pattern of incomplete activation characterized by enhanced CD25 expression but reduced interleukin 2 production. The same pattern of incomplete lymphocyte activation was observed in CD4 ؉ T cells responding to HCV core in patients with chronic HCV infection. However, CD4؉ response to HCV core was normal in patients who cleared HCV after alpha interferon therapy. Moreover, a normal CD4 ؉ response to tetanus toxoid was found in both chronic HCV carriers and patients who had eliminated the infection. Our results suggest that expression of HCV structural antigens in infected DC disturbs their antigen-presenting function, leading to incomplete activation of anti-HCV-specific T cells and chronicity of infection. However, presentation of unrelated antigens by noninfected DC would allow normal T-cell immunity to other pathogens.Hepatitis C virus (HCV) is a single-stranded RNA virus belonging to the Flaviviridae family (25). Although some patients exhibit acute self-limited infection, a characteristic feature of HCV is the high incidence of persistent infection and chronic hepatitis, with a strong risk for the development of hepatocellular carcinoma (10). This high incidence of chronicity suggests that the virus has developed efficient mechanisms to escape host immune responses. Indeed, although most patients have anti-HCV antibodies (38), cellular immune responses are weak in chronically infected patients. It has been reported that CD4 ϩ T-cell responses against viral antigens are vigorous in individuals who have cleared HCV after acute infection or after treatment with alpha interferon (IFN-␣) (11,21,26,35). By contrast, patients who fail to respond to therapy exhibit poor T-cell reactivity against viral proteins. Regarding CD8 ϩ lymphocytes, low responses have been detected in infected patients (7,32,37), and recent reports show that these cells play a critical role during the acute phase of the disease (8). Thus, chronicity of HCV infection is related to the inability of HCV-specific CD4 ϩ and CD8 ϩ T cells to accomplish efficient effector functions. These defects, however, are not the result of general immunosuppression since T-cell immunity to other pathogens is well preserved in patients with chronic HCV infection.HCV may evade immune surveillance by different mechanisms including mutations in regions that are targets for the immune system (13,40,41)...

Hepatitis C virus-specific reactivity of CD4+-lymphocytes in children born from HCV-infected women

“…Therefore, CD4C-cells from the mothers appeared to respond to HCV antigens with incomplete activation, characterized by normal levels of IL-2 secretion and CD25 (IL-2 receptor) expression, but low levels of proliferation. Incomplete activation of HCV-specific T-cells in chronically infected patients had been previously described by other Authors and ascribed to abnormal priming of CD4CT-cells specific to structural proteins by dendritic cells infected by HCV [19,20]. We suggest that production of high levels of IL-10 early upon stimulation with HCV-antigens may represent an additional mechanism underlying the incomplete activation of HCV-specific lymphocytes in chronically infected individuals.…”

Enhancement of CD4 and CD8 immunity by anti-CD137 (4-1BB) monoclonal antibodies during hepatitis C vaccination with recombinant adenovirus

“…In fact, the frequency of CTL precursors against HCV proteins found in patients with chronic hepatitis C is very low, in comparison to that found in HIV or CMV infections [46][47][48]. It has been described that HCV can infect DC and that expression of HCV proteins inside DC induces an impairment of its stimulatory functions [20] and this impairment might lead an inefficient priming of anti-HCV T cell responses [19,29,49]. Thus, there is a need for the development of strategies able to induce potent immune responses against HCV proteins that could be effective in the treatment and prevention of HCV infection.…”

“…However, when the dose of RAdNS3 was reduced to 5 × 10 8 pfu, only a marginal induction of anti-NS3 T cell responses were detected and no protection against vHCV1-3011 challenge was elicited. It has been recently described that HCV proteins might impair dendritic cell differentiation and mediate an immunoinhibitory effect on the induction of anti-HCV immune responses [18][19][20]. Thus, strategies aimed at augmenting the immunogenicity of the recombinant adenovirus expressing NS3 might have important implications for a potential anti-HCV vaccine.…”

Fusion of HBsAg and prime/boosting augment Th1 and CTL responses to HCV polytope DNA vaccine

“…However, most HCV DNA vaccines failed to elicit protective responses due to the utilization of a complete antigen with limited numbers of dominant CTL epitopes, which are also faced with immune escape through antigenic variation [8]. Besides, presence of suppressive regions within the complete antigen may interfere with the function of dominant epitopes, as shown for structural and NS3 proteins of HCV, resulting in functional subversion of T cells, natural killer and dendritic cells [5;8;9].…”