Disc Large Homolog 1 Is Critical for Early T Cell Receptor Micro Cluster Formation and Activation in Human T Cells.
Disc Large Homolog 1 Is Critical for Early T Cell Receptor Micro Cluster Formation and Activation in Human T Cells.
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DOI：
10.3390/vaccines9121446
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发表时间：
2021-12-07
期刊：
影响因子：
7.8
通讯作者：
Chari R
中科院分区：
文献类型：
--
作者：
Guha J;Chari R
抗原激活T细胞涉及多个步骤，包括T细胞受体-微簇TCR-(MC)的形成、免疫突触的形成以及TCR下游介质的磷酸化。已知的适配器蛋白Disc Large Homolog 1(DLG1)调节近端的TCR信号，进而调节T细胞的激活，充当分子伴侣，在抗原识别下游组织特定的激酶。在这项研究中，我们使用人类原代T细胞和一株人类T细胞株的基因敲除和基因敲除技术来证明DLG1在近端T细胞信号转导中的作用。高端共聚焦显微镜用于T细胞微簇的图示和共定位研究。从这些研究中，我们可以证明DLG1的功能甚至比免疫突触形成更早，通过促进TCR-MC的形成来调节T细胞的激活。此外，我们还发现DLG1可以作为TcR-ζ链和ZAP70之间的桥梁，同时抑制磷酸酶SHP1与TcR-ζ的结合。总而言之，这些效应导致DLG1缺陷T细胞中T细胞激活的失调。总体而言，T细胞的激活和存活状态是有效疫苗应答的关键决定因素，DLG1介导的T细胞信号事件可能是改进疫苗设计策略的驱动因素。
T cell activation by antigen involves multiple sequential steps, including T cell receptor-microcluster TCR-(MC) formation, immunological synapse formation, and phosphorylation of mediators downstream of the TCR. The adaptor protein, Disc Large Homolog 1 (DLG1), is known to regulate proximal TCR signaling and, in turn, T cell activation, acting as a molecular chaperone that organizes specific kinases downstream of antigen recognition. In this study, we used knockdown and knockout technologies in human primary T cells and a human T cell line to demonstrate the role of DLG1 in proximal T cell signaling. High-end confocal microscopy was used for pictorial representation of T cell micro-clusters and colocalization studies. From all these studies, we could demonstrate that DLG1 functions even earlier than immunological synapse formation, to regulate T cell activation by promoting TCR-MC formation. Moreover, we found that DLG1 can act as a bridge between the TCR-ζ chain and ZAP70 while inhibiting binding of the phosphatase SHP1 to TCR-ζ. Together, these effects drive dysregulation of T cell activation in DLG1-deficient T cells. Overall, the activation and survival status of T cell is a critical determinant of effective vaccine response, and DLG1-mediated T cell signaling events can be a driving factor for improving vaccine-designing strategies.
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影响因子：
3.7
作者：
Humphries LA;Shaffer MH;Sacirbegovic F;Tomassian T;McMahon KA;Humbert PO;Silva O;Round JL;Takamiya K;Huganir RL;Burkhardt JK;Russell SM;Miceli MC
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影响因子：
30.5
作者：
Choi S;Warzecha C;Zvezdova E;Lee J;Argenty J;Lesourne R;Aravind L;Love PE
通讯作者：
Love PE
影响因子：
8.7
作者：
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通讯作者：
Lorenz U
影响因子：
32.4
作者：
Nagaishi, Takashi;Pao, Lily;Blumberg, Richard S.
通讯作者：
Blumberg, Richard S.
影响因子：
32.4
作者：
Ludford-Menting, MJ;Oliaro, J;Russell, SM
通讯作者：
Russell, SM