PDF(Pubmed)
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.
摘要：
逆转CD8+T细胞功能障碍是治疗慢性乙型肝炎病毒（HBV）感染的关键，然而具体的分子靶标仍不清楚.我们的研究分析了肝细胞引发过程中的共信号受体，并追踪了功能失调的HBV特异性CD8+T细胞的轨迹和命运。早期,这些细胞上调PD-1，CTLA-4，LAG-3，OX40，4-1BB，和ICOS。虽然阻断共抑制受体的作用很小，激活4-1BB和OX40将它们转化为抗病毒效应物。长时间的刺激导致自我更新，长寿,具有独特转录谱的异质群体。这包括功能失调的祖细胞/干细胞样(TSL)细胞和两个不同的功能失调的组织驻留记忆(TRM)群体。虽然4-1BB表达普遍存在，OX40表达仅限于TSL。在慢性环境中，只有4-1BB刺激赋予抗病毒活性。在HBeAg+慢性患者，4-1BB活化显示出恢复功能失调的CD8+T细胞的最高潜力。靶向所有功能失调的T细胞，而不仅仅是茎状前体，有望治疗慢性HBV感染。
