Group of Innate Immunity, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany;
Department of Immunobiochemistry, Centre for Biomedicine and Medical Technology (CBTM), Medical Faculty Mannheim, Heidelberg University, 68167 Mannheim, Germany.
Proc Natl Acad Sci U S A. 2018 Jun 26;115(26):E5980-E5989. doi: 10.1073/pnas.1720564115. Epub 2018 Jun 12.
CD8 T cells are considered prototypical cells of adaptive immunity. Here, we uncovered a distinct CD8 T cell population expressing the activating natural killer (NK) receptor NKp30 in the peripheral blood of healthy individuals. We revealed that IL-15 could de novo induce NKp30 expression in a population of CD8 T cells and drive their differentiation toward a broad innate transcriptional landscape. The adaptor FcεRIγ was concomitantly induced and was shown to be crucial to enable NKp30 cell-surface expression and function in CD8 T cells. FcεRIγ de novo expression required promoter demethylation and was accompanied by acquisition of the signaling molecule Syk and the "innate" transcription factor PLZF. IL-15-induced NKp30CD8 T cells exhibited high NK-like antitumor activity in vitro and were able to synergize with T cell receptor signaling. Importantly, this population potently controlled tumor growth in a preclinical xenograft mouse model. Our study, while blurring the borders between innate and adaptive immunity, reveals a unique NKp30FcεRIγCD8 T cell population with high antitumor therapeutic potential.
CD8 T 细胞被认为是适应性免疫的典型细胞。在这里，我们在健康个体的外周血中发现了一种表达激活自然杀伤 (NK) 受体 NKp30 的独特 CD8 T 细胞群体。我们揭示了白细胞介素 15 (IL-15) 可以在 CD8 T 细胞群体中诱导 NKp30 的表达，并促使它们向广泛的先天转录谱分化。衔接蛋白 FcεRIγ 同时被诱导，并被证明对 NKp30 细胞表面表达和功能在 CD8 T 细胞中至关重要。FcεRIγ 的新表达需要启动子去甲基化，并伴随着获得信号分子 Syk 和“先天”转录因子 PLZF。IL-15 诱导的 NKp30+CD8 T 细胞在体外表现出高 NK 样抗肿瘤活性，并能与 T 细胞受体信号协同作用。重要的是，该群体在临床前异种移植小鼠模型中能够有效地控制肿瘤生长。我们的研究虽然模糊了先天免疫和适应性免疫之间的界限，但揭示了一种具有高抗肿瘤治疗潜力的独特的 NKp30+FcεRIγ+CD8 T 细胞群体。
