IL-15 boosts activated HBV core-specific CD8⁺ progenitor cells via metabolic rebalancing in persistent HBV infection

A rebalance between energy supply and demand in HBV-specific-CD8⁺ activated progenitor (AP) cells could restore the functionality of proliferative progeny (PP) in e-antigen(Ag)-negative chronic hepatitis B (CHBe(-)). We observed that quiescent progenitor (QP [TCF1⁺/FSC^low]) HBVcore-specific-CD8⁺ cells displayed a memory-like phenotype. Following Ag-encounter, the generated AP [TCF1⁺/FSC^high] subset maintained the PD1⁺/CD127⁺ phenotype and gave rise to proliferative progeny (PP [ TCF1^-/FSC^high]). In AP cells, IL-15 compared to IL2 decreased the initial mTORC1 boost, but maintained its activation longer linked to a catabolic profile that correlated with enhanced PP effector abilities. In nucleos(t)ide analogue (NUC)-treated CHBe(-), AP subset showed an anabolic phenotype associated with a dysfunctional PP pool. In CHBe(-) cases with low probability of HBVcore-specific-CD8⁺ cell on-NUC-treatment restoration, according to a clinical predictive model, IL-15/anti-PD-L1 treatment re-established their reactivity. Therefore, IL-15 could improve AP pool energy balance by decreasing intensity but extending T cell activation and by inducing a more catabolic metabolism.