TNF-α/IFN-γ profile of HBV-specific CD4 T cells is associated with liver damage and viral clearance in chronic HBV infection.

BACKGROUND & AIMS: The role of Hepatitis B virus (HBV)-specific CD4 T cells in chronic HBV infection patients is not clear.

METHODS: Through intracellular IFN-γ and TNF-α staining, HBV-specific CD4 T cells were analyzed in 68 chronic HBV infection patients with alanine aminotransferase (ALT) < 2×upper limit of normal (ULN) and 28 hepatitis B flare patients. HBV-specific HLA-DRB1*0803/HLA-DRB1*1202-restricted CD4 T-cell epitopes were identified.

RESULTS: TNF-α producing cells were the dominant population in patients' HBV-specific CD4 T cells. In patients with ALT < 2×ULN, both the frequency and the dominance of HBV-specific IFN-γ producing CD4 T cells increased sequentially in patients with elevated levels of viral clearance: HBeAg positive, HBeAg negative, and HBsAg negative. In hepatitis B flare patients, the frequency of HBV core-specific TNF-α producing CD4 T cells was positively correlated with patients' ALT and total bilirubin level, and the frequency of those cells changed in parallel with the severity of liver damage. Patients with HBeAg/HBsAg loss after flare showed higher frequency and dominance of HBV-specific IFN-γ producing CD4 T cells, compared to patients without HBeAg/HBsAg loss. Both the frequency and the dominance of HBV S-specific IFN-γ producing CD4 T cells were positively correlated with the decrease of HBsAg during flare. A differentiation process from TNF-α producing cell to IFN-γ producing cell in HBV-specific CD4 T cells was observed during flare. Eight and 9 HBV-derived peptides/pairs were identified as HLA-DRB1*0803 restricted epitopes and HLA-DRB1*1202 restricted epitopes, respectively.

CONCLUSIONS: HBV-specific TNF-α producing CD4 T cells is associated with liver damage, while HBV-specific IFN-γ producing CD4 T cells is associated with viral clearance in chronic HBV infection patients.

LAY SUMMARY: TNF-α producing cells are the dominant population of HBV-specific CD4 T cells in chronic HBV infection patients, and this population might contribute to the aggravation of liver damage in hepatitis B flare patients. HBV-specific IFN-γ producing CD4 T cells are associated with HBV viral clearance. Differentiation from HBV-specific TNF-α producing CD4 T cells into HBV-specific IFN-γ producing CD4 T cells might favor HBV viral clearance.