αβ-T细胞受体转导赋予γδ-T细胞卓越的线粒体功能并有希望持久存在。
αβ-T cell receptor transduction gives superior mitochondrial function to γδ-T cells with promising persistence.
发表日期：2023 Oct 20
作者：
Mikiya Ishihara, Hiroshi Miwa, Hiroshi Fujiwara, Yasushi Akahori, Takuma Kato, Yoshimasa Tanaka, Isao Tawara, Hiroshi Shiku
来源：
CYTOKINE & GROWTH FACTOR REVIEWS
摘要：
采用异基因γδ-T细胞的细胞治疗是具有低移植物抗宿主病(GVHD)风险的现成T细胞产品的一个有前途的选择。长期存留可能促进γδ-T细胞产品的临床发展。在本研究中，我们发现表达肿瘤抗原特异性αβ-TCR和CD8共受体的遗传修饰的Vγ9+Vδ2+ T细胞(GMC)表现出特异性杀伤和优秀的存留。为了确定这些有前途的效果的机制，我们研究了其代谢特征。γδ-TCR刺激的非基因修饰的γδ-T细胞(NGMCs)和αβ-TCR刺激的GMCs的细胞因子分泌受到糖酵解抑制剂的同样抑制，然而，αβ-TCR刺激的GMCs的细胞因子分泌被ATP合酶抑制剂抑制的程度比γδ-TCR刺激的NGMCs更强。代谢组学、转录组学分析、使用线粒体标记染料的流式细胞仪分析和细胞外通量分析一致表明，αβ-TCR转导的γδ-T细胞获取了更优秀的线粒体功能。总之，αβ-TCR转导的γδ-T细胞具有具有良好持久性的优秀线粒体功能。© 2023 作者。
Adoptive cell therapy using allogeneic γδ-T cells is a promising option for off-the-shelf T cell products with a low risk of graft-versus-host disease (GVHD). Long-term persistence may boost the clinical development of γδ-T cell products. In this study, we found that genetically modified Vγ9+Vδ2+ T cells expressing a tumor antigen-specific αβ-TCR and CD8 coreceptor (GMC) showed target-specific killing and excellent persistence. To determine the mechanisms underlying these promising effects, we investigated metabolic characteristics. Cytokine secretion by γδ-TCR-stimulated nongene-modified γδ-T cells (NGMCs) and αβ-TCR-stimulated GMCs was equally suppressed by a glycolysis inhibitor, although the cytokine secretion of αβ-TCR-stimulated GMCs was more strongly inhibited by ATP synthase inhibitors than that of γδ-TCR-stimulated NGMCs. Metabolomic and transcriptomic analyses, flow cytometry analysis using mitochondria-labeling dyes and extracellular flux analysis consistently suggest that αβ-TCR-transduced γδ-T cells acquire superior mitochondrial function. In conclusion, αβ-TCR-transduced γδ-T cells acquire superior mitochondrial function with promising persistence.© 2023 The Authors.