Alpha E beta 7 integrin interaction with E-cadherin promotes antitumor CTL activity by triggering lytic granule polarization and exocytosis.
Alpha E beta 7 integrin interaction with E-cadherin promotes antitumor CTL activity by triggering lytic granule polarization and exocytosis.
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Alpha E Beta 7与E-钙粘着蛋白的整合素相互作用通过触发裂解颗粒极化和胞吐作用来促进抗肿瘤CTL活性。
DOI：
10.1084/jem.20061524
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发表时间：
2007-03-19
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多种T细胞粘附分子及其同源受体在靶细胞上促进T细胞受体介导的细胞杀伤。在本报告中，我们证明上皮细胞标志物E-cadherin与整合素αE(CD103)β7的相互作用，通常由肿瘤浸润淋巴细胞（TILs）表达，在有效的肿瘤细胞裂解中起主要作用。事实上，我们发现尽管肿瘤特异性CD103+ til衍生的细胞毒性T淋巴细胞（CTL）克隆能够杀死E-cadherin+/细胞间粘附分子1 -自体肿瘤细胞，但CD103 -外周血淋巴细胞（PBL）衍生的细胞毒性T淋巴细胞（CTL）克隆效率低下。在使用阻断性抗cd103单克隆抗体治疗TIL克隆或使用核糖核酸干扰靶向肿瘤中的E-cadherin后，这种细胞杀伤被取消。共聚焦显微镜分析还表明，α e - β7在免疫突触被募集，并且它与E-cadherin的相互作用是细胞溶解颗粒极化和随后的胞外分泌所必需的。此外，我们报道了CD103 -谱，在pbl衍生的CTL克隆中经常观察到，并且与同源肿瘤的细胞毒性差相关，在TCR参与和转化生长因子β1治疗后上调，导致抗肿瘤裂解功能的增强。因此，浸润上皮肿瘤的CD8+/CD103+肿瘤反应性T淋巴细胞很可能通过α e - β7 - e -钙粘蛋白相互作用在抗肿瘤细胞毒性反应中发挥主要作用。
Various T cell adhesion molecules and their cognate receptors on target cells promote T cell receptor (TCR)–mediated cell killing. In this report, we demonstrate that the interaction of epithelial cell marker E-cadherin with integrin αE(CD103)β7, often expressed by tumor-infiltrating lymphocytes (TILs), plays a major role in effective tumor cell lysis. Indeed, we found that although tumor-specific CD103+ TIL-derived cytotoxic T lymphocyte (CTL) clones are able to kill E-cadherin+/intercellular adhesion molecule 1− autologous tumor cells, CD103− peripheral blood lymphocyte (PBL)-derived counterparts are inefficient. This cell killing is abrogated after treatment of the TIL clones with a blocking anti-CD103 monoclonal antibody or after targeting E-cadherin in the tumor using ribonucleic acid interference. Confocal microscopy analysis also demonstrated that αEβ7 is recruited at the immunological synapse and that its interaction with E-cadherin is required for cytolytic granule polarization and subsequent exocytosis. Moreover, we report that the CD103− profile, frequently observed in PBL-derived CTL clones and associated with poor cytotoxicity against the cognate tumor, is up-regulated upon TCR engagement and transforming growth factor β1 treatment, resulting in strong potentiation of antitumor lytic function. Thus, CD8+/CD103+ tumor-reactive T lymphocytes infiltrating epithelial tumors most likely play a major role in antitumor cytotoxic response through αEβ7–E-cadherin interactions.