Introduction

The arrest of rolling T lymphocytes at specific locations is crucial to proper immune response function. We previously developed a model of chemokine-driven integrin activation, termed integrative signaling adhesive dynamics (ISAD). In addition, we have shown that loss of diacylglycerol kinase (DGK) leads to a gain of function regarding adhesion under shear flow. We undertook this study to understand the sensitivity of adhesion to perturbations in other signaling molecules.

Methods

We adapted multi-parametric sensitivity analysis (MPSA) for use in our ISAD model to identify important parameters, including initial protein concentrations and kinetic rate constants, for T lymphocyte arrest. We also compared MPSA results to those obtained from a single parametric sensitivity analysis.

Results

In addition to the previously shown importance of DGK in lymphocyte arrest, PIP₂ cleavage and Rap1 activation are crucial in determining T cell arrest dynamics, which agree with previous experimental findings. The l-selectin density on the T lymphocyte surface also plays a large role in determining the distance rolled before arrest. Both the MPSA and single-parametric method returned similar results regarding the most sensitive kinetic rate constants.

Conclusion

We show here that the regulation of the amount of second messengers are, in general, more critical for determining T lymphocyte arrest over the initial signaling proteins, highlighting the importance of amplification of signaling in cell adhesion responses. Overall, this work provides a mechanistic insight of the contribution of key pathways and components, thus may help to identify potential therapeutic targets for drug development against immune disorders.

中文翻译：

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使用多参数全局敏感性分析识别趋化因子触发的 T 淋巴细胞阻滞动力学中的关键途径和成分。

介绍

滚动 T 淋巴细胞在特定位置的停滞对于适当的免疫反应功能至关重要。我们之前开发了一种趋化因子驱动的整合素激活模型，称为整合信号粘附动力学 (ISAD)。此外，我们已经表明，二酰基甘油激酶 (DGK) 的损失导致在剪切流下的粘附功能获得。我们进行了这项研究，以了解粘附对其他信号分子扰动的敏感性。

方法

我们采用多参数敏感性分析 (MPSA) 用于我们的 ISAD 模型，以确定 T 淋巴细胞停滞的重要参数，包括初始蛋白质浓度和动力学速率常数。我们还将 MPSA 结果与从单参数灵敏度分析中获得的结果进行了比较。

结果

除了先前显示的 DGK 在淋巴细胞停滞中的重要性之外，PIP ₂裂解和 Rap1 激活对于确定 T 细胞停滞动力学至关重要，这与之前的实验结果一致。T 淋巴细胞表面的l-选择素密度在确定停止前滚动的距离方面也起着重要作用。MPSA 和单参数方法都返回了关于最敏感的动力学速率常数的相似结果。

结论

我们在这里表明，第二信使数量的调节通常对于确定 T 淋巴细胞比初始信号蛋白的停滞更为关键，突出了信号放大在细胞粘附反应中的重要性。总体而言，这项工作提供了对关键途径和成分的贡献的机制洞察，因此可能有助于确定针对免疫疾病的药物开发的潜在治疗靶点。