CD8 T cells specific to apoptosis-associated epitopes are expanded in patients with chronic HBV infection and fibrosis.

Background & Aims: During chronic viral infections, the apoptosis of activated T cell elicits a CD8 T cell response directed to those cryptic epitopes that emerge from caspase-cleaved structural proteins. Such response directed to apoptosis-associated epitopes (AEs) contributes to the amplification of immunopathology.

Methods: Here, we have analysed through flow cytometry AE-specific CD8 T cells in patients with chronic hepatitis B virus (HBV) infection, naïve-to-treatment or undergoing nucleos(t)ide-analogue (NUC) therapy.

Results: We found that AE-specific CD8 T cell frequencies were significantly increased only in those NUC-treated patients who also presented advanced hepatic fibrosis. Regulatory T cells were also expanded in those patients, and AE-specific, but not HBV-specific, CD8 T cell frequency positively correlated with Treg percentages. Through multiparameter flow cytometry, multidimensionality reduction and unsupervised clustering analysis, we could identify novel subpopulations among effector memory (em) and emCD45RA T cell (Tem and Temra) subsets. CD8 T cells with distinct specificities differentially populated the subpopulation map: while HBV-specific were mostly contained in the Tem subset, AE-specific CD8 T cells encompassed naïve, as well as T central memory, Tem and Temra cells.

Conclusion: All together, these findings indicate a link between AE-specific CD8 T cells and advanced liver fibrosis in patients with chronic HBV infection, and suggest that virus-specific and AE-specific CD8 T cells exhibit distinct differentiation states and contribute in distinct ways to immunopathology.