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
Affiliations
Julia Peña-Asensio
Department of Biology of Systems, University of Alcalá, 28801 Alcalá de Henares, Madrid, Spain; Instituto de Investigación Sanitaria de Castilla La-Mancha (IDISCAM), 45071 Toledo, Castilla La-Mancha, Spain
Henar Calvo-Sánchez
Section of Gastroenterology, Guadalajara University Hospital, 19002 Guadalajara, Castilla La-Mancha, Spain; Department of Medicine & Medical Specialties, University of Alcalá, 28801 Alcalá de Henares, Madrid, Spain; Instituto de Investigación Sanitaria de Castilla La-Mancha (IDISCAM), 45071 Toledo, Castilla La-Mancha, Spain
Joaquín Miquel
Section of Gastroenterology, Guadalajara University Hospital, 19002 Guadalajara, Castilla La-Mancha, Spain; Instituto de Investigación Sanitaria de Castilla La-Mancha (IDISCAM), 45071 Toledo, Castilla La-Mancha, Spain
Eduardo Sanz-de-Villalobos
Section of Gastroenterology, Guadalajara University Hospital, 19002 Guadalajara, Castilla La-Mancha, Spain; Instituto de Investigación Sanitaria de Castilla La-Mancha (IDISCAM), 45071 Toledo, Castilla La-Mancha, Spain
Alejandro González-Praetorius
Section of Microbiology, Guadalajara University Hospital, 19002 Guadalajara, Castilla La-Mancha, Spain; Instituto de Investigación Sanitaria de Castilla La-Mancha (IDISCAM), 45071 Toledo, Castilla La-Mancha, Spain
Miguel Torralba
Service of Internal Medicine, Guadalajara University Hospital, 19002 Guadalajara, Castilla La-Mancha, Spain; Department of Medicine & Medical Specialties, University of Alcalá, 28801 Alcalá de Henares, Madrid, Spain; Instituto de Investigación Sanitaria de Castilla La-Mancha (IDISCAM), 45071 Toledo, Castilla La-Mancha, Spain
Juan-Ramón Larrubia
Section of Gastroenterology, Guadalajara University Hospital, 19002 Guadalajara, Castilla La-Mancha, Spain; Department of Medicine & Medical Specialties, University of Alcalá, 28801 Alcalá de Henares, Madrid, Spain; Instituto de Investigación Sanitaria de Castilla La-Mancha (IDISCAM), 45071 Toledo, Castilla La-Mancha, Spain; Corresponding author
Summary: 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+/FSClow]) HBVcore-specific-CD8+ cells displayed a memory-like phenotype. Following Ag-encounter, the generated AP [TCF1+/FSChigh] subset maintained the PD1+/CD127+ phenotype and gave rise to proliferative progeny (PP [ TCF1-/FSChigh]). 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.
