Laboratory of Experimental Tumour Immunology, Department of Medical Oncology, Erasmus MC-Daniel den Hoed Cancer Center, Groene Hilledijk 301, 3075 EA, Rotterdam, The Netherlands.
Cancer Immunol Immunother. 2010 Jun;59(6):921-31. doi: 10.1007/s00262-010-0818-0. Epub 2010 Jan 26.
IL-21, and to a lesser extent IL-15, inhibits differentiation of antigen-primed CD8 T cells and promotes their homeostasis and anti-tumour activity. Here, we investigated molecular mechanisms behind tumour-specific responses of primary murine T lymphocytes engineered to express a TCR directed against human gp100/HLA-A2 following short-term exposure to IL-15 and/or IL-21. We demonstrated that IL-15 + IL-21, and to a lesser extent IL-21, enhanced antigen-specific T-cell cytotoxicity, which was related to enhanced expression of granzymes A and B, and perforin 1. Furthermore, IL-15 + IL-21 synergistically enhanced release levels and kinetics of T-cell IFNgamma and IL-2, but not IL-10. Enhanced secretion of IFNgamma was accompanied by increased gene expression and cytosolic protein content, and was restricted to effector memory T cells. To summarize, we show that IL-15 + IL-21 improves antigen-specific responses of TCR-transduced effector T cells at multiple levels, which provides a rationale to treat T cells with a combination of these cytokines prior to their use in adoptive TCR gene therapy.
白细胞介素-21（IL-21），在一定程度上还有白细胞介素-15（IL-15），可抑制抗原激活的 CD8 T 细胞的分化，并促进其自身稳定和抗肿瘤活性。在此，我们研究了经过短期暴露于 IL-15 和/或 IL-21 后，针对人 gp100/HLA-A2 的 TCR 进行基因工程改造的原代小鼠 T 淋巴细胞的肿瘤特异性反应背后的分子机制。我们证明，IL-15 + IL-21，在一定程度上还有 IL-21，增强了抗原特异性 T 细胞的细胞毒性，这与颗粒酶 A 和 B 以及穿孔素 1 的表达增强有关。此外，IL-15 + IL-21 协同增强 T 细胞 IFNγ和 IL-2 的释放水平和动力学，但不增强 IL-10。IFNγ 的分泌增强伴随着基因表达和胞质蛋白含量的增加，并且仅限于效应记忆 T 细胞。总之，我们表明，IL-15 + IL-21 可在多个层面改善 TCR 转导的效应 T 细胞的抗原特异性反应，这为在过继性 TCR 基因治疗前用这些细胞因子联合治疗 T 细胞提供了依据。
