Muraoka Daisuke, Seo Naohiro, Hayashi Tae, Hyuga-Amaike Chisaki, Okamori Kana, Tawara Isao, Harada Naozumi, Shiku Hiroshi
Department of Immuno-Gene Therapy, Mie University Graduate School of Medicine, Mie, Japan.
Center for Drug Discovery, Graduate School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, Japan.
Oncotarget. 2017 May 9;8(19):30766-30780. doi: 10.18632/oncotarget.15403.
Long-surviving memory CD8+ T cells generated by stimulation with appropriate tumor-associated antigens are the most aggressive and persistent tumoricidal effectors. In this event of memory CD8+ T cell development, the signal transducer and activator of transcription (STAT) proteins function as the crucial intracellular signaling molecules, but the regulatory mechanism of STATs in CD8+ T cells is not fully understood. In this study, we report for the first time, by using murine vaccination models, that signal-transducing adaptor protein-2 (STAP2) maintains the cytotoxicity of long-lived memory CD8+ T cells by controlling a STAT3/suppressor of cytokine signaling 3 (SOCS3) cascade. Following T cell activation, STAP2 expression was transiently reduced but was subsequently recovered and augmented. Analysis using small-interfering RNA (siRNA) demonstrated that restored STAP2 expression was associated with the activation of STAT3/SOCS3 signals and maintenance of cytotoxic T lymphocytes (CTLs) secondary responses by preventing their differentiation into terminal effector cells. Notably, this STAP2-dependent memory differentiation was observed in the spleen, but not in the lymph nodes (LNs). These findings indicate an essential role for STAP2 in the generation of a high-quality memory CD8+ CTLs periphery, and suggest the therapeutic potential of STAP2 in cancer patients.
通过用适当的肿瘤相关抗原刺激产生的长期存活的记忆性CD8 + T细胞是最具攻击性和持久性的杀瘤效应细胞。在记忆性CD8 + T细胞发育过程中，信号转导及转录激活蛋白（STAT）发挥关键的细胞内信号分子作用，但STATs在CD8 + T细胞中的调控机制尚未完全明确。在本研究中，我们首次利用小鼠疫苗接种模型报道，信号转导衔接蛋白2（STAP2）通过控制STAT3 /细胞因子信号转导抑制因子3（SOCS3）级联反应来维持长寿记忆性CD8 + T细胞的细胞毒性。T细胞活化后，STAP2表达短暂降低，但随后恢复并增强。使用小干扰RNA（siRNA）进行的分析表明，恢复的STAP2表达与STAT3 / SOCS3信号的激活以及通过防止细胞毒性T淋巴细胞（CTLs）分化为终末效应细胞来维持其二次反应有关。值得注意 的是，这种依赖STAP2的记忆分化在脾脏中观察到，而在淋巴结（LN）中未观察到。这些发现表明STAP2在高质量记忆性CD8 + CTLs外周生成中起重要作用，并提示STAP2在癌症患者中的治疗潜力。
