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

Abstract 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.