Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, 1649-028 Lisbon, Portugal.
J Immunol. 2014 Mar 1;192(5):2237-43. doi: 10.4049/jimmunol.1303119. Epub 2014 Jan 31.
Cytotoxicity and IFN-γ production by human γδ T cells underlie their potent antitumor functions. However, it remains unclear where and how human γδ T cells acquire these key effector properties. Given the recent disclosure of a major contribution of the thymus to murine γδ T cell functional differentiation, in this study we have analyzed a series of human pediatric thymuses. We found that ex vivo-isolated γδ thymocytes produced negligible IFN-γ and lacked cytolytic activity against leukemia cells. However, these properties were selectively acquired upon stimulation with IL-2 or IL-15, but not IL-4 or IL-7. Unexpectedly, TCR activation was dispensable for these stages of functional differentiation. The effects of IL-2/IL-15 depended on MAPK/ERK signaling and induced de novo expression of the transcription factors T-bet and eomesodermin, as well as the cytolytic enzyme perforin, required for the cytotoxic type 1 program. These findings have implications for the manipulation of γδ T cells in cancer immunotherapy.
人 γδ T 细胞的细胞毒性和 IFN-γ 产生是其强大抗肿瘤功能的基础。然而，人 γδ T 细胞如何获得这些关键效应功能仍不清楚。鉴于最近揭示了胸腺对鼠 γδ T 细胞功能分化的重大贡献，在这项研究中，我们分析了一系列人儿童胸腺。我们发现，体外分离的 γδ 胸腺细胞几乎不产生 IFN-γ，对白血病细胞也没有细胞毒性。然而，这些特性在受到 IL-2 或 IL-15 的刺激时会被选择性地获得，但受到 IL-4 或 IL-7 的刺激时则不会。出乎意料的是，TCR 激活对于这些功能分化阶段是可有可无的。IL-2/IL-15 的作用依赖于 MAPK/ERK 信号通路，并诱导转录因子 T-bet 和 eomesodermin 的从头表达，以及细胞毒性酶穿孔素的表达，这些都是细胞毒性 1 型程序所必需的。这些发现对癌症免疫治疗中 γδ T 细胞的操作具有重要意义。
