An integrated stochastic model of "inside-out" integrin activation and selective T-lymphocyte recruitment.
An integrated stochastic model of "inside-out" integrin activation and selective T-lymphocyte recruitment.
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DOI：
10.1021/la203803e
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发表时间：
2012-01-31
期刊：
影响因子：
--
通讯作者：
Hammer DA
中科院分区：
文献类型：
--
作者：
Beste MT;Lee D;King MR;Koretzky GA;Hammer DA
T淋巴细胞归巢的模式被认为是由趋化因子受体和补充性趋化因子共同控制的。在这里，我们使用数值模拟来探索趋化因子的效力与浓度、信号转导和黏附之间的关系。我们开发了一种粘合动力学形式--一种机械上精确的粘合随机模拟--它结合了使用NEXT子体积法的随机信号转导。我们表明，使用来自各种来源的可测量参数估计，包括允许我们训练参数值的信号测量，我们可以很容易地模拟T淋巴细胞停止的近似时间尺度。我们发现，当多个趋化因子受体通过单个G蛋白传递时，粘附性与总趋化因子受体的占有率相关，而不是与占有率相关。选择性T淋巴细胞募集的一般策略似乎需要低亲和力的趋化因子受体。对于单个趋化因子受体，多个交叉反应趋化因子的增加可以导致粘附性的压倒性增加。总体而言，本文提出的方法为了解趋化因子对T淋巴细胞募集的控制提供了一个预测性框架。
The pattern of T lymphocyte homing is hypothesized to be controlled by combnations of chemokine receptors and complementary chemokines. Here, we use numerical simulation to explore the relationship among chemokine potency and concentration, signal transduction, and adhesion. We have developed a form of Adhesive Dynamics – a mechanically accurate stochastic simulation of adhesion – that incorporates stochastic signal transduction using the next subvolume method. We show that using measurable parameter estimates derived from a variety of sources, including signaling measurements that allow us to train parameter values, we can readily simulate approximate time scales for T lymphocyte arrest. We find that adhesion correlates with total chemokine receptor occupancy, not the frequency of occupation, when multiple chemokine receptors feed through a single G-protein. A general strategy for selective T-lymphocyte recruitment appears to require low affinity chemokine receptors. For a single chemokine receptor, increases in multiple cross-reactive chemokines can lead to an overwhelming increase in adhesion. Overall, the methods presented here provide a predictive framework for understanding chemokine control of T-lymphocyte recruitment.
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