Diacylglycerol kinase zeta negatively regulates CXCR4-stimulated T lymphocyte firm arrest to ICAM-1 under shear flow.
Diacylglycerol kinase zeta negatively regulates CXCR4-stimulated T lymphocyte firm arrest to ICAM-1 under shear flow.
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二酰基甘油激酶 zeta 负向调节 CXCR4 刺激的 T 淋巴细胞在剪切流下牢固停滞于 ICAM-1。
DOI：
10.1039/c2ib00002d
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发表时间：
2012
期刊：
影响因子：
--
通讯作者：
Hammer,DanielA
中科院分区：
文献类型：
--
作者：
Lee,Dooyoung;Kim,Jiyeon;Beste,MichaelT;Koretzky,GaryA;Hammer,DanielA
微血管内的T淋巴细胞停滞是免疫监视和适应性免疫应答的重要过程。整合素和趋化因子通过趋化因子触发的整合素由内而外的激活来协调调节T细胞在流动下停止的时间和地点。二酰基甘油激酶（DGK）调节二酰基甘油（DAG）的水平，其进而决定鸟嘌呤核苷酸交换因子（GEF）和Ras邻近1（Rap 1）分子的活化，所述分子对整合素淋巴细胞功能相关抗原1（LFA-1）的活化至关重要。然而，DGK的水平如何调节趋化因子刺激的LFA-1介导的T细胞停滞下流动是未知的。使用实验和计算建模的组合，我们证明了DGK β是CXCL 12触发的T细胞在呈递细胞间粘附分子1（ICAM-1）的表面上停滞的关键调节剂。利用流动室实验，我们发现，在不改变滚动速度的情况下，T细胞中DGK受体的缺陷显著增加了对ICAM-1包被的底物的牢固阻滞，并缩短了停止的时间。这些结果表明，DGK β水平影响LFA-1介导的T细胞的牢固停滞，但不影响P-选择素介导的CXCL 12刺激过程中的滚动。我们使用整合信号粘附动力学（ISAD）在计算上准确地模拟了DGK β在T细胞牢固阻滞中的作用。与存在DGK分子时相比，在没有DGK催化反应的情况下，模型细胞在被捕前滚动的时间明显更短。我们的T细胞停滞模型的预测定量匹配实验结果。总之，这些结果表明，DGK β是剪切流下CXCL 12触发的LFA-1由内而外活化和T细胞牢固粘附的负调节剂。
T lymphocyte arrest within microvasculature is an essential process in immune surveillance and the adaptive immune response. Integrins and chemokines coordinately regulate when and where T cells stop under flowviachemokine-triggered inside-out activation of integrins. Diacylglycerol kinases (DGKs) regulate the levels of diacylglycerol (DAG) which in turn determine the activation of guanine nucleotide exchange factors (GEFs) and Ras proximity 1 (Rap1) molecules crucial to the activation of integrin lymphocyte function-associated antigen 1 (LFA-1). However, how the level of DGK regulates chemokine-stimulated LFA-1-mediated T cell arrest under flow is unknown. Using a combination of experiment and computational modeling, we demonstrate that DGKζ is a crucial regulator of CXCL12-triggered T cell arrest on surfaces presenting inter-cellular adhesion molecule 1 (ICAM-1). Using flow chamber assays, we found that the deficiency of DGKζ in T cells significantlyincreasedfirm arrest to ICAM-1-coated substrates and shortened the time to stop without altering the rolling velocity. These results suggest that DGKζ levels affect LFA-1-mediated T cell firm arrest, but not P-selectin-mediated rolling during CXCL12 stimulation. We accurately simulated the role of DGKζ in firm arrest of T cells computationally using an Integrated-Signaling Adhesive Dynamics (ISAD). In the absence of DGK catalytic reaction, the model cells rolled for a significantly shorter time before arrest, compared to when DGK molecules were present. Predictions of our model for T cell arrest quantitatively match experimental results. Overall these results demonstrate that DGKζ is a negative regulator of CXCL12-triggered inside-out activation of LFA-1 and firm adhesion of T cells under shear flow.
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影响因子：
20.3
作者：
Kuwano, Yoshihiro;Spelten, Oliver;Zarbock, Alexander
通讯作者：
Zarbock, Alexander
影响因子：
3.4
作者：
Krasik, Ellen F.;Yee, Ka Lai;Hammer, Daniel A.
通讯作者：
Hammer, Daniel A.
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DOI：
10.1172/jci14151
发表时间：
2002
期刊：
The Journal of clinical investigation.
影响因子：
--
作者：
Xia,Lijun;Sperandio,Markus;Yago,Tadayuki;McDaniel,JMichael;Cummings,RichardD;Pearson-White,Sonia;Ley,Klaus;McEver,RodgerP
通讯作者：
McEver,RodgerP
影响因子：
3.4
作者：
Chang, KC;Hammer, DA
通讯作者：
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影响因子：
3.4
作者：
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通讯作者：
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