Redirecting mouse CTL against colon carcinoma: superior signaling efficacy of single-chain variable domain chimeras containing TCR-zeta vs Fc epsilon RI-gamma.
Redirecting mouse CTL against colon carcinoma: superior signaling efficacy of single-chain variable domain chimeras containing TCR-zeta vs Fc epsilon RI-gamma.
复制标题
重定向小鼠 CTL 对抗结肠癌：含有 TCR-zeta 的单链可变结构域嵌合体与 Fc epsilon RI-gamma 相比，其信号传导功效更佳。
作者：
N. Haynes;M. B. Snook;J. Trapani;L. Cerruti;S. Jane;M. Smyth;P. Darcy
结构上相关的TCR-Zeta和Fc-IgE受体(Fc Epsilon RI)-γ分别是TCR和Fc epsilon RI的重要信号成分。尽管含有Zeta和Gamma信号链的嵌合抗体受体已被用于将CTL重定向至肿瘤，但以前还没有对它们的相对有效性进行直接比较。在这里，我们比较了识别癌胚抗原(CEA)的单链可变区(ScFv)嵌合受体中Zeta和Gamma亚基在幼稚T淋巴细胞中的信号传递能力。利用非常有效的逆转录病毒基因传递系统，T细胞表达了高水平和同等水平的ScFv-Zeta和ScFv-Gamma受体。尽管与结肠癌靶细胞的表达水平和抗原特异性结合相似，但连接T细胞上的scFv-抗-CEA-Zeta嵌合受体比通过scFv-抗-CEA-γ受体激活更能产生更多的细胞因子和直接的细胞毒性。表达ScFv-Zeta嵌合受体的T细胞对SCID/SCID小鼠体内的人结肠癌和C57BL/6小鼠体内的小鼠结肠癌均有较强的抑制作用。总体而言，这些数据首次直接比较并明确证明了通过Zeta信号通路激活的T细胞的增强效力。
The structurally related TCR-zeta and Fc receptor for IgE (Fc epsilon RI)-gamma are critical signaling components of the TCR and Fc epsilon RI, respectively. Although chimeric Ab receptors containing zeta and gamma signaling chains have been used to redirect CTL to tumors, a direct comparison of their relative efficacy has not previously been undertaken. Here, in naive T lymphocytes, we compare the signaling capacities of the zeta and gamma subunits within single-chain variable domain (scFv) chimeric receptors recognizing the carcinoembryonic Ag (CEA). Using a very efficient retroviral gene delivery system, high and equivalent levels of scFv-zeta and scFv-gamma receptors were expressed in T cells. Despite similar levels of expression and Ag-specific binding to colon carcinoma target cells, ligation of scFv-anti-CEA-zeta chimeric receptors on T cells resulted in greater cytokine production and direct cytotoxicity than activation via scFv-anti-CEA-gamma receptors. T cells expressing scFv-zeta chimeric receptors had a greater capacity to control the growth of human colon carcinoma in scid/scid mice or mouse colon adenocarcinoma in syngeneic C57BL/6 mice. Overall, these data are the first to directly compare and definitively demonstrate the enhanced potency of T cells activated via the zeta signaling pathway.