Human CD4+ T-cell response to hepatitis delta virus: identification of multiple epitopes and characterization of T-helper cytokine profiles

Abstract

The T-cell-mediated immune response plays a crucial role in defense against hepatotropic viruses as well as in the pathogenesis of viral chronic hepatitides. However, very little is known about the role of specific T cells during hepatitis delta virus (HDV) infection in humans. In this study, the T-cell response to HDV in chronic hepatitis B virus (HBV) carriers with HDV superinfection was investigated at different levels. Analysis of peripheral blood mononuclear cell (PBMC) proliferation in response to a recombinant form of large hepatitis delta antigen (HDAg) revealed that 8 of 30 patients studied (27%) specifically responded to HDAg. By employing synthetic peptides spanning the entire HDAg sequence, we found that T-cell recognition was directed against different antigenic determinants, with patient-to-patient variation in the pattern of response to peptides. Interestingly, all responders had signs of inactive HDV-induced disease, while none of the patients with active disease and none of the control subjects showed any significant proliferation. More accurate information about the specific T-cell response was obtained at the clonal level. A panel of HDAg-specific CD4 ؉ T-cell clones from three HDV-infected individuals and fine-specificity analysis revealed that the clones tested individually recognized four epitopes corresponding to amino acids (aa) 26 to 41, 50 to 65, 66 to 81, or 106 to 121 of HDAg sequence. The study of human leukocyte antigen (HLA) restriction revealed that peptides 50 to 65 and 106 to 121 were presented to specific T cells in association with multiple class II molecules. In addition, peptide 26 to 41 was efficiently generated after processing of HDAg through the endogenous processing pathway. Cytokine secretion analysis showed that all the CD4 ؉ T-cell clones assayed were able to produce high levels of gamma interferon (IFN-␥), belonging either to T helper-1 (Th1) or Th0 subsets and that some of them were cytotoxic in a specific assay. This study provides the first evidence that detection of a specific T-cell response to HDAg in the peripheral blood of individuals with hepatitis delta is related to the decrease of HDV-induced disease activity. The HDAg epitopes identified here and particularly those recognized by CD4 ؉ T cells in association with multiple major histocompatibility complex class II molecules may be potentially exploited for the preparation of a vaccine for prophylaxis and therapy of HDV infection.

DNA-based immunization produces Th1 immune responses to hepatitis delta virus in a mouse model

“…50 Another recent study revealed that the T-cell response to HDAg is related to the activity of HDV-induced liver disease. 13 These findings support the necessity of T-cell immunity to modulate the disease course of HDV infection. As shown by the T-cell proliferation and cytokine assay, the DNA vaccines against HDV did produce cellular immune response with a Th1 preference.…”

“…12 A recent study showed that patients with inactive HDV infection had a significant T-cell proliferation response to HDV synthetic peptides; conversely, patients with active HDV-related hepatitis showed no significant response. 13 It is thus postulated that the host immune response might determine disease activities after HDV infection. 13 Augmentation of the host' s cellular immune response may represent an ideal way to treat chronic HDV infection.…”

“…13 It is thus postulated that the host immune response might determine disease activities after HDV infection. 13 Augmentation of the host' s cellular immune response may represent an ideal way to treat chronic HDV infection.…”

Hepatitis D revival

“…HDV genotype 1 is not cytopathic and thus immune responses probably play an important role in the pathogenesis of HDV-induced liver disease. In a study from Italy, patients with inactive but not active-HDV disease displayed HDV-specific proliferative CD4 responses to HDAg, suggesting that cellular immune responses probably controlled HDV infection (20). Preliminary data suggest that the endogenous interferon (IFN) system is highly activated in hepatitis D. This is supported by results showing that perforin-expressing lymphoid cells including CD4 1 T cells are more frequent in hepatitis D patients than in HBV or HCV monoinfection (21).…”

T‐cell‐mediated and antigen‐dependent differentiation of human monocyte into different dendritic cell subsets: a feedback control of Th1/Th2 responses

“…PPD and Parj1-specific TCCs were derived from peripheral blood mononuclear cells (PBMCs) of a normal donor and maintained in culture as described previously (39) with some variations. In particular, cultures were set up in the presence or absence of 100 U/ml IL-4 (40) to obtain Th2 TCCs.…”