Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195.
Proc Natl Acad Sci U S A. 2014 Feb 11;111(6):2265-70. doi: 10.1073/pnas.1317431111. Epub 2014 Jan 27.
Because cytokine-priming signals direct CD8(+) T cells to acquire unique profiles that affect their ability to mediate specific immune responses, here we generated IL-9-skewed CD8(+) T (Tc9) cells by priming with Th9-polarized condition. Compared with type-I CD8(+) cytotoxic T (Tc1) cells, Tc9 secreted different cytokines and were less cytolytic in vitro but surprisingly elicited greater antitumor responses against advanced tumors in OT-I/B16-OVA and Pmel-1/B16 melanoma models. After adoptive transfer, Tc9 cells persisted longer and differentiated into IFN-γ- and granzyme-B (GrzB)-producing cytolytic Tc1-like effector cells. Phenotypic analysis revealed that adoptively transferred Tc9 cells secreted IL-2 and were KLRG-1(low) and IL-7Rα(high), suggesting that they acquired a signature of "younger" phenotype or became long-term lived cells with capacity of self-renewal. Our results also revealed that Tc9-mediated therapeutic effect critically depended on IL-9 production in vivo. These findings have clinical implications for the improvement of CD8(+) T-cell-based adoptive immunotherapy of cancers.
由于细胞因子引发信号会引导 CD8(+)T 细胞获得独特的表型，从而影响其介导特定免疫反应的能力，因此我们通过 Th9 极化条件的诱导产生了偏向于分泌白细胞介素-9（IL-9）的 CD8(+)T（Tc9）细胞。与 I 型 CD8(+)细胞毒性 T（Tc1）细胞相比，Tc9 细胞分泌的细胞因子不同，体外细胞毒性较低，但令人惊讶的是，在 OT-I/B16-OVA 和 Pmel-1/B16 黑色素瘤模型中，它们对晚期肿瘤引发了更强的抗肿瘤反应。在过继转移后，Tc9 细胞持续存在时间更长，并分化为产生 IFN-γ 和颗粒酶 B（GrzB）的细胞毒性 Tc1 样效应细胞。表型分析显示，过继转移的 Tc9 细胞分泌 IL-2，且 KLRG-1（低）和 IL-7Rα（高），表明它们获得了“年轻”表型的特征或成为具有自我更新能力的长期存活细胞。我们的研究结果还表明，Tc9 介导的治疗效果在很大程度上取决于体内的 IL-9 产生。这些发现对改善基于 CD8(+)T 细胞的癌症过继免疫疗法具有临床意义。
