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. [ABSTRACT FROM AUTHOR]