CD103 or LFA-1 Engagement at the Immune Synapse between Cytotoxic T Cells and Tumor Cells Promotes Maturation and Regulates T-cell Effector Functions
CD103 or LFA-1 Engagement at the Immune Synapse between Cytotoxic T Cells and Tumor Cells Promotes Maturation and Regulates T-cell Effector Functions
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DOI：
10.1158/0008-5472.can-12-2569
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发表时间：
2013-01-15
期刊：
影响因子：
11.2
通讯作者：
Mami-Chouaib, Fathia
中科院分区：
文献类型：
--
作者：
Franciszkiewicz, Katarzyna;Le Floc'h, Audrey;Mami-Chouaib, Fathia
T细胞粘附/共刺激分子及其在靶细胞上的同源受体在T细胞受体（TCR）介导的活性中起主要作用。在这里，我们比较了参与CD 103和LFA-1，和它们各自的配体，在细胞毒性免疫突触（cIS）的成熟和CTL效应功能的激活。我们的研究结果表明，对癌细胞的细胞毒性，并在较小程度上，细胞因子的生产，由特定的CTL需要，连同TCR的参与，无论是CD 103与E-钙粘蛋白或LFA-1与ICAM-1的相互作用。基于流动的粘附测定显示，CD 103或LFA-1与TCR一起的接合增强了T细胞/靶细胞相互作用的强度。此外，电子显微镜分析表明，整合素依赖性成熟的cIS（mcIS）显示出一个有凝聚力的超微结构，与广泛的裂缝分开的紧密的膜接触。相比之下，无法触发靶细胞溶解的未成熟cIS（icIS）较松散，效应细胞膜上有多个突起。使用共聚焦显微镜的实验揭示了与靶细胞杀伤相关的mcIS处的极化细胞因子释放和脱粒，而icIS的特征在于IFN-γ和颗粒酶B重新定位的失败。因此，CTL和上皮肿瘤细胞之间的相互作用力，主要由整合素参与调节，与成熟和cIS的超微结构相关，并影响CTL效应子功能。这些结果为调节抗肿瘤CTL应答的分子机制提供了新的见解，并可能导致更有效的癌症免疫治疗策略的发展。Cancer Res; 73（2）; 617-28.（C）2012年AACR。
T-cell adhesion/costimulatory molecules and their cognate receptors on target cells play a major role in T-cell receptor (TCR)-mediated activities. Here, we compared the involvement of CD103 and LFA-1, and their respective ligands, in the maturation of the cytotoxic immune synapse (cIS) and in the activation of CTL effector functions. Our results indicate that cytotoxicity toward cancer cells and, to a lesser extent, cytokine production by specific CTL require, together with TCR engagement, the interaction of either CD103 with E-cadherin or LFA-1 with ICAM-1. Flow-based adhesion assay showed that engagement of CD103 or LFA-1, together with TCR, enhances the strength of the T-cell/target cell interaction. Moreover, electron microscopic analyses showed that integrin-dependent mature cIS (mcIS) displays a cohesive ultrastructure, with tight membrane contacts separated by extensive clefts. In contrast, immature cIS (icIS), which is unable to trigger target cell lysis, is loose, with multiple protrusions in the effector cell membrane. Experiments using confocal microscopy revealed polarized cytokine release and degranulation at the mcIS associated with target cell killing, whereas icIS is characterized by failure of IFN-gamma and granzyme B relocalization. Thus, interactive forces between CTL and epithelial tumor cells, mainly regulated by integrin engagement, correlate with maturity and the ultrastructure of the cIS and influence CTL effector functions. These results provide new insights into molecular mechanisms regulating antitumor CTL responses and may lead to the development of more efficient cancer immunotherapy strategies. Cancer Res; 73(2); 617-28. (C)2012 AACR.