Insufficient deactivation of the protein tyrosine kinase lck amplifies T-cell responsiveness in acute coronary syndrome.
Insufficient deactivation of the protein tyrosine kinase lck amplifies T-cell responsiveness in acute coronary syndrome.
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DOI：
10.1161/circresaha.109.206052
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发表时间：
2010-03-05
影响因子：
20.1
通讯作者：
Weyand CM
中科院分区：
文献类型：
--
作者：
Pryshchep S;Goronzy JJ;Parashar S;Weyand CM
在易损的动脉粥样硬化斑块中，T细胞可能通过直接的细胞损伤效应功能破坏组织结构的稳定。T细胞通过调节细胞质蛋白的磷酸化将环境信号（例如抗原识别）传递到细胞反应中; Src家族激酶Lck位于T细胞受体（TCR）信号级联的关键近膜位置。蛋白质磷酸化和去磷酸化之间的平衡定义了信号转导阈值，并决定了适当的T细胞反应。我们研究了细胞内信号通路的异常校准是否会使ACS患者对不成比例的T细胞反应敏感。在用MHC II-超抗原复合物刺激后，对ACS患者和对照个体的CD 4 T细胞中的细胞内信号级联进行了定量。ACS T细胞比对照T细胞动员更多的细胞内钙和积累更高水平的磷酸酪氨酸。TCR信号传导的近端步骤，如ZAP-70的募集和免疫突触中TCR复合物的聚集，在ACS T细胞中异常增强。加速源自ACS T细胞中近端缺陷的信号级联，其未能磷酸化Lck atTyr 505，延长Src激酶的活化。TCR信号传导的异常与C反应蛋白测量的全身性炎症无关。ACS T细胞的信号传导机制中的内在异常导致活性Lck的积累，降低了TCR阈值，并使淋巴细胞反应过度，能够产生不需要的免疫应答。
In the vulnerable atherosclerotic plaque, T cells may destabilize the tissue structure through direct cell-injurious effector functions. T cells transmit environmental signals, such as recognition of antigen, into cellular responses through regulated phosphorylation of cytoplasmic proteins; with the Src family kinase Lck in critical membrane-proximal position of the T-cell receptor (TCR) signaling cascade. The balance between protein phosphorylation and dephosphorylation defines the signal transduction threshold and determines appropriate T-cell responses. We have examined whether abnormal calibration of intracellular signaling pathways renders ACS patients susceptible to disproportionate T-cell responses. Intracellular signaling cascades were quantified in CD4 T cells from ACS patients and control individuals after stimulation with MHC II-superantigen complexes. ACS T cells mobilized more intracellular calcium and accumulated higher levels of phosphotyrosine than control T cells. Proximal steps in TCR signaling, such as recruitment of ZAP-70 and clustering of TCR complexes in the immune synapse, were abnormally enhanced in ACS T cells. Acceleration of the signaling cascade derived from a proximal defect in ACS T cells, which failed to phosphorylate Lck atTyr505, extending activation of the Src kinase. Abnormalities in TCR signaling did not correlate with systemic inflammation as measured by C-reactive protein. An intrinsic abnormality in the signaling machinery of ACS T cells resulting in the accumulation of active Lck lowers the TCR threshold and renders lymphocytes hyperreactive and capable of unwanted immune responses.