Cell · 2024
Therapeutic potential of co-signaling receptor modulation in hepatitis B.
СтатьяНазвание и аннотация: Перевод в очереди
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Andreata Francesco, Laura Chiara, Ravà Micol, Krueger Caroline C, Ficht Xenia, Kawashima Keigo, Beccaria Cristian G, Moalli Federica, Partini Bianca, Fumagalli Valeria, Nosetto Giulia, Di Lucia Pietro, Montali Ilaria, Garcia-Manteiga José M, Bono Elisa B, Giustini Leonardo, Perucchini Chiara, Venzin Valentina, Ranucci Serena, Inverso Donato, De Giovanni Marco, Genua Marco, Ostuni Renato, Lugli Enrico, Isogawa Masanori, Ferrari Carlo, Boni Carolina, Fisicaro Paola, Guidotti Luca G, Iannacone Matteo
Аннотация
Reversing CD8+ T cell dysfunction is crucial in treating chronic hepatitis B virus (HBV) infection, yet specific molecular targets remain unclear. Our study analyzed co-signaling receptors during hepatocellular priming and traced the trajectory and fate of dysfunctional HBV-specific CD8+ T cells. Early on, these cells upregulate PD-1, CTLA-4, LAG-3, OX40, 4-1BB, and ICOS. While blocking co-inhibitory receptors had minimal effect, activating 4-1BB and OX40 converted them into antiviral effectors. Prolonged stimulation led to a self-renewing, long-lived, heterogeneous population with a unique transcriptional profile. This includes dysfunctional progenitor/stem-like (TSL) cells and two distinct dysfunctional tissue-resident memory (TRM) populations. While 4-1BB expression is ubiquitously maintained, OX40 expression is limited to TSL. In chronic settings, only 4-1BB stimulation conferred antiviral activity. In HBeAg+ chronic patients, 4-1BB activation showed the highest potential to rejuvenate dysfunctional CD8+ T cells. Targeting all dysfunctional T cells, rather than only stem-like precursors, holds promise for treating chronic HBV infection.