IL12-mediated sensitizing of T-cell receptor-dependent and -independent tumor cell killing
IL12-mediated sensitizing of T-cell receptor-dependent and -independent tumor cell killing
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DOI：
10.1080/2162402x.2016.1188245
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发表时间：
2016-01-01
期刊：
影响因子：
7.2
通讯作者：
Woelfl, Matthias
中科院分区：
文献类型：
--
作者：
Braun, Matthias;Ress, Marie L.;Woelfl, Matthias
白细胞介素12（IL 12）是一种关键的炎症细胞因子，在初始抗原接触时对Th 1/Tc 1-T细胞应答有重要影响。因此，它可以用于癌症免疫治疗。在这里，我们研究了IL 12和其他炎性细胞因子如何塑造人类T细胞的效应子功能。使用确定的培养系统，我们跟踪了抗原特异性CD 8（+）T细胞的逐渐分化和功能，从它们作为初始T细胞的初始活化到它们作为早期记忆细胞的扩增阶段，再到作为克隆扩增的效应T细胞的完全分化。在初始引发事件后8天添加IL 12引发了两个机制上独立的事件：首先，IL 12使T细胞受体（TCR）对抗原特异性活化敏感，导致肽敏感性增加约10倍，从而增强肿瘤细胞杀伤。其次，IL 12能够实现TCR/HLA非依赖性活化和细胞毒性：这种“非特异性”效应由NK细胞受体DNAM 1（CD 226）介导，并依赖于靶细胞的配体表达。这种IL 12调节的DNAM 1介导的杀伤依赖于src激酶以及PTPRC（CD 45）活性。因此，除了增强TCR介导的激活外，我们在这里首次确定了IL 12介导的第二种机制，导致通过DNA 1激活受体依赖性杀伤途径。
Interleukin 12 (IL12) is a key inflammatory cytokine critically influencing Th1/Tc1-T-cell responses at the time of initial antigen encounter. Therefore, it may be exploited for cancer immunotherapy. Here, we investigated how IL12, and other inflammatory cytokines, shape effector functions of human T-cells. Using a defined culture system, we followed the gradual differentiation and function of antigen-specific CD8(+) T cells from their initial activation as naive T cells through their expansion phase as early memory cells to full differentiation as clonally expanded effector T cells. The addition of IL12 8 days after the initial priming event initiated two mechanistically separate events: First, IL12 sensitized the T-cell receptor (TCR) for antigen-specific activation, leading to an approximately 10-fold increase in peptide sensitivity and, in consequence, enhanced tumor cell killing. Secondly, IL12 enabled TCR/HLA-independent activation and cytotoxicity: this "non-specific" effect was mediated by the NK cell receptor DNAM1 (CD226) and dependent on ligand expression of the target cells. This IL12 regulated, DNAM1-mediated killing is dependent on src-kinases as well as on PTPRC (CD45) activity. Thus, besides enhancing TCR-mediated activation, we here identified for the first time a second IL12 mediated mechanism leading to activation of a receptor-dependent killing pathway via DNAM1.