GADS is required for TCR-mediated calcium influx and cytokine release, but not cellular adhesion, in human T cells.
GADS is required for TCR-mediated calcium influx and cytokine release, but not cellular adhesion, in human T cells.
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DOI：
10.1016/j.cellsig.2015.01.012
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发表时间：
2015-04
影响因子：
4.8
通讯作者：
Houtman JC
中科院分区：
文献类型：
--
作者：
Bilal MY;Zhang EY;Dinkel B;Hardy D;Yankee TM;Houtman JC
GRB 2相关的Shc下游衔接蛋白（GADS）是GRB 2衔接子家族的成员，对TCR诱导的信号传导至关重要。目前的模型是GADS将SLP-76募集到LAT复合物中，这促进了SLP-76的磷酸化、PLC-γ1的活化、T细胞粘附和细胞因子的产生。然而，该模型主要基于GADS/SLP-76相互作用的破坏和GADS缺陷小鼠中的鼠T细胞分化的研究。GADS在人CD 4 + T细胞中介导TCR诱导信号的作用尚未得到彻底研究。在这项研究中，我们抑制了人CD 4 + HuT 78 T细胞中GADS的表达。GADS缺陷型HuT 78 T细胞显示出相似水平的TCR诱导的SLP-76和PLC-γ1磷酸化，但表现出TCR诱导的IL-2和IFN-γ释放的显著降低。细胞因子产生的缺陷是由于SLP-76和PLC-γ1向LAT复合物的募集减少而导致钙动员受损。令人惊讶的是，当与对照T细胞相比时，GADS缺陷型HuT 78和GADS缺陷型原代鼠CD 8 + T细胞具有相似的TCR诱导的粘附。总的来说，我们的研究结果表明，GADS是所需的钙流入和细胞因子的生产，但不是细胞粘附，在人CD 4 + T细胞，这表明目前的模型T细胞的GADS调节是不完整的。
GRB2 related adaptor protein downstream of Shc (GADS) is a member of the GRB2 family of adaptors and is critical for TCR-induced signaling. The current model is that GADS recruits SLP-76 to the LAT complex, which facilitates the phosphorylation of SLP-76, the activation of PLC-γ1, T cell adhesion and cytokine production. However, this model is largely based on studies of disruption of the GADS/SLP-76 interaction and murine T cell differentiation in GADS deficient mice. The role of GADS in mediating TCR-induced signals in human CD4+ T cells has not been thoroughly investigated. In this study, we have suppressed the expression of GADS in human CD4+ HuT78 T cells. GADS deficient HuT78 T cells displayed similar levels of TCR-induced SLP-76 and PLC-γ1 phosphorylation but exhibited substantial decrease in TCR-induced IL-2 and IFN-γ release. The defect in cytokine production occurred because of impaired calcium mobilization due to reduced recruitment of SLP-76 and PLC-γ1 to the LAT complex. Surprisingly, both GADS deficient HuT78 and GADS deficient primary murine CD8+ T cells had similar TCR-induced adhesion when compared to control T cells. Overall, our results show that GADS is required for calcium influx and cytokine production, but not cellular adhesion, in human CD4+ T cells, suggesting that the current model for T cell regulation by GADS is incomplete.
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影响因子：
4.4
作者：
Houtman, JCD;Houghtling, RA;Samelson, LE
通讯作者：
Samelson, LE
影响因子：
5.3
作者：
Pauker, Maor H.;Reicher, Barak;Barda-Saad, Mira
通讯作者：
Barda-Saad, Mira
DOI：
10.4049/jimmunol.1301587
发表时间：
2013-12-15
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Chapman NM;Connolly SF;Reinl EL;Houtman JC
通讯作者：
Houtman JC
影响因子：
7.2
作者：
Balagopalan, Lakshmi;Coussens, Nathan P.;Sommers, Connie L.
通讯作者：
Sommers, Connie L.
影响因子：
3.7
作者：
Bartelt RR;Cruz-Orcutt N;Collins M;Houtman JC
通讯作者：
Houtman JC