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) SL ) cells and two distinct dysfunctional tissue-resident memory (TRM) RM ) populations. While 4-1BB expression is ubiquitously maintained, OX40 expression is limited to TSL. SL . 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.
Therapeutic potential of co-signaling receptor modulation in hepatitis B / 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. - In: CELL. - ISSN 1097-4172. - 187:15(2024). [10.1016/j.cell.2024.05.038]
Therapeutic potential of co-signaling receptor modulation in hepatitis B
Andreata, Francesco;Laura, Chiara;Beccaria, Cristian G;Partini, Bianca;Fumagalli, Valeria;Perucchini, Chiara;Venzin, Valentina;Inverso, Donato;De Giovanni, Marco;Ostuni, Renato;Guidotti, Luca G;Iannacone, Matteo
2024-01-01
Abstract
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) SL ) cells and two distinct dysfunctional tissue-resident memory (TRM) RM ) populations. While 4-1BB expression is ubiquitously maintained, OX40 expression is limited to TSL. SL . 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.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
