Intravital imaging of CTLs killing islet cells in diabetic mice
Intravital imaging of CTLs killing islet cells in diabetic mice
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DOI：
10.1172/jci59285
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发表时间：
2012-01-01
影响因子：
15.9
通讯作者：
von Herrath, Matthias
中科院分区：
文献类型：
--
作者：
Coppieters, Ken;Amirian, Natalie;von Herrath, Matthias
1型糖尿病（T1 D）是由胰岛中产生胰岛素的β细胞的自身免疫性破坏引起的，胰岛本质上是嵌入外分泌组织中的微型器官。CTL被认为在T1 D基础的自身免疫破坏中具有主要作用。CTL介导的β细胞杀伤的可视化将为T1 D的发病机制提供新的见解，但在技术上难以实现。在这里，我们报告我们使用活体2-光子成像在小鼠中可视化的动态行为的病毒扩增，致糖尿病的CTL群体在胰腺细胞分辨率。在血管停滞和外渗后，CTL在整个紧凑的外分泌组织中采用随机运动模式，并在解剖学上邻近的胰岛之间显示出不受阻碍但非线性的迁移。在胰岛内遇到抗原时，获得了限制的运动模式，允许CTL扫描靶细胞表面。少数浸润性CTL随后在β细胞连接处停滞，而稳定的CTL-靶细胞接触的持续时间为数小时。在持续存在大量效应细胞的情况下，发生缓慢的杀伤。总的来说，这些数据描绘的动力学CTL归巢和抗原靶位点之间作为一个随机过程，在亚器官水平和反对趋化梯度的主导影响。
Type 1 diabetes (T1D) is caused by autoimmune destruction of the insulin-producing beta cells in the pancreatic islets, which are essentially mini-organs embedded in exocrine tissue. CTLs are considered to have a predominant role in the autoimmune destruction underlying T1D. Visualization of CTL-mediated killing of beta cells would provide new insight into the pathogenesis of T1D, but has been technically challenging to achieve. Here, we report our use of intravital 2-photon imaging in mice to visualize the dynamic behavior of a virally expanded, diabetogenic CTL population in the pancreas at cellular resolution. Following vascular arrest and extravasation, CTLs adopted a random motility pattern throughout the compact exocrine tissue and displayed unimpeded yet nonlinear migration between anatomically nearby islets. Upon antigen encounter within islets, a confined motility pattern was acquired that allowed the CTLs to scan the target cell surface. A minority of infiltrating CTLs subsequently arrested at the beta cell junction, while duration of stable CTL-target cell contact was on the order of hours. Slow-rate killing occurred in the sustained local presence of substantial numbers of effector cells. Collectively, these data portray the kinetics of CTL homing to and between antigenic target sites as a stochastic process at the sub-organ level and argue against a dominant influence of chemotactic gradients.