Yamaguchi T, Suzuki Y, Katakura R, Ebina T, Yokoyama J, Fujimiya Y
Division of Immunology, Miyagi Cancer Center Research Institute, Natori City, Japan.
Cancer Immunol Immunother. 1998 Oct;47(2):97-103. doi: 10.1007/s002620050509.
GammadeltaT cells play a regulatory role in both primary and metastatic tumor growth in humans. The mechanisms responsible for the activation and proliferation of circulating gammadeltaT cells should be fully understood prior to their adoptive transfer to cancer patients. We have examined in vitro functional effects of interleukin-15 (IL-15) on highly purified gammadeltaT cells isolated from glioblastoma patients. GammadeltaT cells constitutively express the heterotrimeric IL-2 receptor (IL-2R) alpha betagamma, but the levels of IL-2Rbeta or gamma expression were not increased by incubation with saturating amounts of IL-15. IL-15 was shown to induce a maximal gammadeltaT cell proliferation, although at much higher concentrations (at least 2000 U/ml) than IL-2 (100 U/ml). Submaximal concentrations of IL-15 plus low concentrations of IL-2 produced an additive proliferative response. In contrast to the IL-2-induced response, this activity was completely or partially abrogated by anti-IL-2Rbeta, or anti-IL-2Rgamma antibodies, but not by anti-IL-2R alpha antibodies. Incubation of gammadeltaT cells in the presence of IL-15 resulted not only in the appearance of NK and LAK activity, but also in specific autologous tumor cell killing activity, an additive effect being seen with IL-15 and IL-2. This IL-15-induced tumor-specific activity could be significantly blocked by anti-IL-2Rgamma and anti-IL-2R-beta mAb, but not by anti-IL-2R alpha mAb. Thus, in contrast to IL-2, IL-15 activates tumor-specific gammadeltaT cells through the components of IL-2Rbeta and IL-2Rgamma, but not IL-2R alpha. These enhanced in vitro tumor-specific and proliferative responses of gammadeltaT cells seen with IL-15 suggest a rational adjuvant imunotherapeutic use of gammadeltaT cells in cancer patients.
γδT细胞在人类原发性和转移性肿瘤生长中均发挥调节作用。在将循环γδT细胞过继转移给癌症患者之前，应充分了解负责其激活和增殖的机制。我们已经研究了白细胞介素-15（IL-15）对从胶质母细胞瘤患者分离出的高度纯化γδT细胞的体外功能作用。γδT细胞组成性表达异源三聚体白细胞介素-2受体（IL-2R）αβγ，但用饱和量的IL-15孵育后，IL-2Rβ或γ的表达水平并未增加。已表明IL-15可诱导γδT细胞最大程度的增殖，尽管其浓度（至少2000 U/ml）远高于IL-2（100 U/ml）。亚最大浓度的IL-15加上低浓度的IL-2产生了累加的增殖反应。与IL-2诱导的反应相反，这种活性被抗IL-2Rβ或抗IL-2Rγ抗体完全或部分消除，但抗IL-2Rα抗体则无此作用。在IL-15存在下孵育γδT细胞不仅导致自然杀伤（NK）和淋巴因子激活的杀伤细胞（LAK）活性出现，还导致特异性自体肿瘤细胞杀伤活性，IL-15和IL-2呈现累加效应。这种IL-15诱导的肿瘤特异性活性可被抗IL-2Rγ和抗IL-2R-β单克隆抗体显著阻断，但抗IL-2Rα单克隆抗体则无此作用。因此，与IL-2相反，IL-15通过IL-2Rβ和IL-2Rγ成分而非IL-2Rα激活肿瘤特异性γδT细胞。IL-15所见的γδT细胞这些体外增强的肿瘤特异性和增殖反应提示γδT细胞在癌症患者中进行合理的辅助免疫治疗应用。
