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

Julia Peña-Asensio; Henar Calvo-Sánchez; Joaquín Miquel; Eduardo Sanz-de-Villalobos; Alejandro González-Praetorius; Miguel Torralba; Juan-Ramón Larrubia

doi:10.1016/j.isci.2023.108666

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

iScience. 2023 Dec 7;27(1):108666. doi: 10.1016/j.isci.2023.108666. eCollection 2024 Jan 19.

Authors

Julia Peña-Asensio^{1

2}, Henar Calvo-Sánchez^{3

4

2}, Joaquín Miquel^{3

2}, Eduardo Sanz-de-Villalobos^{3

2}, Alejandro González-Praetorius^{5

2}, Miguel Torralba^{6

4

2}, Juan-Ramón Larrubia^{3

4

2}

Affiliations

¹ Department of Biology of Systems, University of Alcalá, 28801 Alcalá de Henares, Madrid, Spain.
² Instituto de Investigación Sanitaria de Castilla La-Mancha (IDISCAM), 45071 Toledo, Castilla La-Mancha, Spain.
³ Section of Gastroenterology, Guadalajara University Hospital, 19002 Guadalajara, Castilla La-Mancha, Spain.
⁴ Department of Medicine & Medical Specialties, University of Alcalá, 28801 Alcalá de Henares, Madrid, Spain.
⁵ Section of Microbiology, Guadalajara University Hospital, 19002 Guadalajara, Castilla La-Mancha, Spain.
⁶ Service of Internal Medicine, Guadalajara University Hospital, 19002 Guadalajara, Castilla La-Mancha, Spain.

Abstract

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.

Keywords: Biological sciences; Microbiology; Virology.