An Integrated Stochastic Model of 鈥淚nside-Out鈥?Integrin Activation and Selective T-Lymphocyte Recruitment

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• 作者：Michael T. Beste ; Dooyoung Lee ; Michael R. King ; Gary A. Koretzky ; Daniel A. Hammer
• 刊名：Langmuir
• 出版年：2012
• 出版时间：January 31, 2012
• 年：2012
• 卷：28
• 期：4
• 页码：2225-2237
• 全文大小：727K
• 年卷期：v.28,no.4(January 31, 2012)
• ISSN：1520-5827

文摘

The pattern of T-lymphocyte homing is hypothesized to be controlled by combinations 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鈥攁 mechanically accurate stochastic simulation of adhesion鈥攖hat 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 test 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.