Protein kinase CO regulates stability of the peripheral adhesion ring junction and contributes to the sensitivity of target cell lysis by CTL
Protein kinase CO regulates stability of the peripheral adhesion ring junction and contributes to the sensitivity of target cell lysis by CTL
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DOI：
10.4049/jimmunol.181.7.4815
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发表时间：
2008-10-01
影响因子：
4.4
通讯作者：
Sykulev, Yuri
中科院分区：
文献类型：
--
作者：
Beal, Allison M.;Anikeeva, Nadia;Sykulev, Yuri
通过CTL破坏病毒感染的细胞是一个极其敏感和有效的过程。我们以前的数据表明，LFA-1-ICAM-1的相互作用在外周超分子激活簇（pSMAC）的免疫突触介导的紧密粘附连接，可能有助于通过CTL的靶细胞裂解的敏感性的形成。在此，我们比较了更多（CD 8（+））和更少（CD 4（+））有效的CTL以理解促进有效靶细胞裂解的分子事件。我们发现，pSMAC形成的消除显著损害了CD 8（+）而不是CD 4（+）CTL裂解靶细胞的能力，尽管CD 8（+）和CD 4（+）CTL释放颗粒的量没有影响。与此一致，CD 4（+）CTL比CD 8（+）CTL更经常地破坏它们的突触，这导致溶细胞分子从界面逃逸。用蛋白激酶CO抑制剂处理CD 4（+）CTL可增加突触稳定性和特异性靶细胞裂解的敏感性。因此，部分由蛋白激酶CO控制的稳定pSMAC的形成起到将释放的裂解分子限制在突触界面并增强靶细胞裂解的有效性的作用。
Destruction of virus-infected cells by CTL is an extremely sensitive and efficient process. Our previous data suggest that LFA-1-ICAM-1 interactions in the peripheral supramolecular activation cluster (pSMAC) of the immunological synapse mediate formation of a tight adhesion junction that might contribute to the sensitivity of target cell lysis by CTL. Herein, we compared more (CD8(+)) and less (CD4(+)) effective CTL to understand the molecular events that promote efficient target cell lysis. We found that abrogation of the pSMAC formation significantly impaired the ability of CD8(+) but not CD4(+) CTL to lyse target cells despite having no effect of the amount of released granules by both CD8(+) and CD4(+) CTL. Consistent with this, CD4(+) CTL break their synapses more often than do CD8(+) CTL, which leads to the escape of the cytolytic molecules from the interface. CD4(+) CTL treatment with a protein kinase CO inhibitor increases synapse stability and sensitivity of specific target cell lysis. Thus, formation of a stable pSMAC, which is partially controlled by protein kinase CO, functions to confine the released lytic molecules at the synaptic interface and to enhance the effectiveness of target cell lysis.