意大利IRCCS圣拉斐尔科学研究所Matteo Iannacone团队揭示联合信号受体调节对乙型肝炎的治疗潜力。该研究于2024年6月18日在线发表于国际一流学术期刊《细胞》。

研究人员分析了肝细胞启动过程中的协同信号受体，并追踪了功能失调的乙型肝炎病毒（HBV）特异性CD8⁺ T细胞的轨迹和命运。在早期，这些细胞会上调PD-1、CTLA-4、LAG-3、OX40、4-1BB和ICOS。阻断共抑制受体的作用微乎其微，而激活4-1BB和OX40则可将它们转化为抗病毒效应因子。长时间的刺激会导致一种具有独特转录特征的自我更新、长寿命、异质性群体。这包括功能失调的祖细胞/类干细胞（TSL）和两种不同的功能失调的组织驻留记忆（TRM）群体。

虽然4-1BB的表达普遍存在，但OX40的表达仅限于TSL。在慢性环境中，只有4-1BB刺激才具有抗病毒活性。在HBeAg⁺慢性患者中，4-1BB激活显示出使功能失调的CD8⁺ T细胞恢复活力的最大潜力。靶向所有功能失调的T细胞，而不仅仅是干细胞样前体，有望治疗慢性HBV感染。

据悉，逆转CD8⁺ T细胞功能障碍是治疗慢性HBV感染的关键，但具体的分子靶点仍不清楚。

附：英文原文

Title: Therapeutic potential of co-signaling receptor modulation in hepatitis B

Author: Francesco Andreata, Chiara Laura, Micol Ravà, Caroline C. Krueger, Xenia Ficht, Keigo Kawashima, Cristian G. Beccaria, Federica Moalli, Bianca Partini, Valeria Fumagalli, Giulia Nosetto, Pietro Di Lucia, Ilaria Montali, José M. Garcia-Manteiga, Elisa B. Bono, Leonardo Giustini, Chiara Perucchini, Valentina Venzin, Serena Ranucci, Donato Inverso, Marco De Giovanni, Marco Genua, Renato Ostuni, Enrico Lugli, Masanori Isogawa, Carlo Ferrari, Carolina Boni, Paola Fisicaro, Luca G. Guidotti, Matteo Iannacone

Issue&Volume: 2024-06-18

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) 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.

DOI: 10.1016/j.cell.2024.05.038

Source: https://www.cell.com/cell/fulltext/S0092-8674(24)00582-8