Division of Molecular and Life Science, Integrative Bioscience and Biotechnology, WCU, Pohang University of Science and Technology, Pohang, Kyungbuk, Republic of Korea.
J Immunother. 2011 Apr;34(3):297-306. doi: 10.1097/CJI.0b013e318210ed0e.
Programmed death 1 (PD-1) signaling through its ligands, PD-L1 and PD-L2, has been known to negatively regulate T-cell responses. In addition, PD-L1 has been shown to interact with B7-1 costimulatory molecule to inhibit T-cell responses. Extensive studies have shown that PD-1/PD-L blockade restores exhausted T cells during chronic viral infections and tumors. In this study, we evaluated the effects of soluble PD-1 (sPD-1) as a blockade of PD-1 and PD-L1 on vaccine-elicited antigen-specific T-cell responses in mice. Coadministration of sPD-1 DNA with human papilloma virus-16 E7 DNA vaccine significantly enhanced E7-specific CD8(+) T-cell responses, resulting in potent antitumor effects against E7-expressing tumors. We also found that sPD-1, codelivered with adenovirus-based vaccine, could increase antigen-specific CD8(+) T-cell responses, indicating vaccine type-independent adjuvant effect of sPD-1. In addition, the frequency and functional activity of adoptively transferred OT-I cells, particularly memory CD8(+) T cells, were augmented by coadministration of sPD-1 DNA, which was closely associated with increased T-cell proliferation and reduced T-cell apoptosis through upregulation of Bcl-xL expression during T-cell activation. Codelivery of sPD-1 DNA also enhanced maturation of dendritic cells (DCs) in vivo which was accompanied by upregulation of DC maturation markers such as major histocompatibility complex class II. Taken together, our findings show that sPD-1 potently enhances codelivered antigen-specific CD8(+) T-cell responses and in vivo maturation of DCs during activation of naive CD8(+) T cells, suggesting that an immunization strategy with sPD-1 as an adjuvant can be used to increase antigen-specific T-cell immunity elicited by vaccination.
程序性死亡受体 1（PD-1）与其配体 PD-L1 和 PD-L2 的信号传导已被证实可负向调节 T 细胞的反应。此外，PD-L1 已被证实与 B7-1 共刺激分子相互作用以抑制 T 细胞的反应。大量研究表明，PD-1/PD-L 阻断可在慢性病毒感染和肿瘤中恢复耗竭的 T 细胞。在这项研究中，我们评估了可溶性 PD-1（sPD-1）作为 PD-1 和 PD-L1 阻断剂对小鼠中 HPV-16 E7 疫苗诱导的抗原特异性 T 细胞反应的影响。sPD-1 DNA 与 HPV-16 E7 DNA 疫苗共同给药显著增强了 E7 特异性 CD8+T 细胞反应，从而对表达 E7 的肿瘤产生了强大的抗肿瘤作用。我们还发现，sPD-1 与腺病毒疫苗共同给药可以增加抗原特异性 CD8+T 细胞反应，表明 sPD-1 具有与疫苗类型无关的佐剂效应。此外，sPD-1 DNA 的共同给药增加了过继转移的 OT-I 细胞（特别是记忆性 CD8+T 细胞）的频率和功能活性，这与 T 细胞激活过程中通过上调 Bcl-xL 表达而增加 T 细胞增殖和减少 T 细胞凋亡密切相关。sPD-1 DNA 的共同给药还增强了体内树突状细胞（DC）的成熟，这伴随着 DC 成熟标志物如主要组织相容性复合物 II 的上调。总之，我们的研究结果表明，sPD-1 可有效地增强共给药的抗原特异性 CD8+T 细胞反应，并在激活初始 CD8+T 细胞时增强体内 DC 的成熟，提示 sPD-1 作为佐剂的免疫策略可用于增强疫苗接种引起的抗原特异性 T 细胞免疫。
