Involvement of CD70 and CD80 intracytoplasmic domains in the co-stimulatory signal required to provide an antitumor immune response
Involvement of CD70 and CD80 intracytoplasmic domains in the co-stimulatory signal required to provide an antitumor immune response
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DOI：
10.1093/intimm/dxg038
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发表时间：
2003-03-01
影响因子：
4.4
通讯作者：
Couderc, B
中科院分区：
文献类型：
--
作者：
Douin-Echinard, V;Péron, JM;Couderc, B
CD 70和CD 80是分别属于肿瘤坏死因子家族和B7家族的共刺激分子。当它们由基因修饰的TS/A肿瘤细胞共表达时，它们提供有效的保护性和持久的T依赖性抗肿瘤反应。我们首先表明，当CD 70和CD 80通过基因修饰的成纤维细胞在肿瘤环境中递送，但肿瘤细胞本身不表达时，没有观察到抗肿瘤反应。我们接下来评估了CD 70和CD 80的胞质内结构域是否有助于增强诱导有效的T细胞-肿瘤细胞相互作用和T细胞依赖性抗肿瘤应答所必需的共刺激活性。对TS/A细胞进行基因修饰，以表达缺失的（CD 70 Delta和CD 80 Delta）或全长CD 70和CD 80共刺激分子的不同组合。在体外，CD 80胞浆内结构域需要通过与肌动蛋白细胞骨架相互作用来调节CD 80膜的再分布。CD 70胞浆内结构域的丢失并没有改变其在表面膜上重新定位的能力，但未能共同刺激T细胞增殖。在同系BALB/c小鼠体内实验表明，CD 70/CD 80-TS/A和CD 70 Delta/CD 80-TS/A肿瘤通过CD 8 T细胞被排斥，而CD 70/CD 80 Delta-TS/A和CD 70 Delta/CD 80 Delta-TS/A肿瘤则没有。与排斥CD 70/CD 80-TS/A肿瘤的小鼠相比，排斥CD 70 Delta/CD 80-TS/A肿瘤的小鼠对注射亲本TS/A细胞的保护作用降低。这些结果表明，CD 80的胞浆内结构域对于CD 8 T细胞依赖性肿瘤排斥的效应期是关键的，并且CD 70胞浆内结构域可以介导最佳效应/记忆CD 8 T细胞产生所需的增殖或存活信号。
CD70 and CD80 are co-stimulatory molecules which belong to the tumor necrosis factor family and the B7 family respectively. When they are co-expressed by gene-modified TS/A tumor cells, they provide an efficient protective and long-lasting T-dependent antitumor response. We first showed that when CD70 and CD80 were delivered in the tumor environment by gene-modified fibroblasts, but were not expressed by the tumor cells themselves, no antitumor response was observed. We next assessed whether the intracytoplasmic domains of CD70 and CD80 contribute to enhance the co-stimulatory activity necessary to induce effective T cell-tumor cell interactions and T cell-dependent antitumor response. TS/A cells were gene-modified to express different combinations of deleted (CD70Delta and CD80Delta) or full-length CD70 and CD80 co-stimulatory molecules. In vitro, the CD80 intracytoplasmic domain was required to regulate CD80 membrane redistribution by interacting with the actin cytoskeleton. The loss of the CD70 intracytoplasmic domain did not alter its ability to relocate on the surface membrane, but failed to co-stimulate T cell proliferation. In vivo experiments in syngeneic BALB/c mice showed that the CD70/CD80-TS/A and the CD70Delta/CD80-TS/A tumors were rejected via CD8 T cells, whereas CD70/CD80Delta-TS/A and CD70Delta/CD80Delta-TS/A tumors were not. The mice that rejected CD70Delta/CD80-TS/A tumors showed decreased protection against injection of parental TS/A cells when compared to mice which rejected CD70/CD80-TS/A tumors. These results showed that the intracytoplasmic domain of CD80 was critical for the effector phase of CD8 T cell-dependent tumor rejection and that the CD70 intracytoplasmic domain could mediate proliferative or surviving signals required for optimal effector/memory CD8 T cell generation.