TCR-induced downregulation of protein tyrosine phosphatase PEST augments secondary T cell responses
TCR-induced downregulation of protein tyrosine phosphatase PEST augments secondary T cell responses
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DOI：
10.1016/j.molimm.2008.03.019
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发表时间：
2008-06-01
影响因子：
3.6
通讯作者：
Mustelin, Tomas
中科院分区：
文献类型：
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作者：
Arimura, Yutaka;Vang, Torkel;Mustelin, Tomas
我们报道了蛋白酪氨酸磷酸酶PTP-PEST在静息的人和小鼠CD 4（+）和CD 8（+）T细胞中表达，但在Jurkat T白血病细胞中不表达，并且PTP-PEST蛋白而不是mRNA在T细胞活化后的CD 4（+）和CD 8（+）原代人T细胞中显著下调。这在小鼠CD 4（+）T细胞中也是如此，但在小鼠CD 8 + T细胞中不太引人注目。PTP-PEST以与原代人T细胞相似的水平重新引入jurkat，是TCR诱导的报告基因反式激活的有效抑制剂，该报告基因由NFAT/AP-1和NF-κ B元件以及整个IL-2基因启动子驱动。将PTP-PEST引入先前活化的原代人T细胞中也减少了这些细胞响应于TCR和CD 28刺激的随后IL-2产生。PTP-PEST的抑制作用与Lck激酶在其激活环位点（Y394）的去磷酸化、减少早期TCR诱导的酪氨酸磷酸化、减少ZAP-70磷酸化和抑制MAP激酶激活有关。我们认为PTP-PEST通过去磷酸化TCR近端信号分子（如Lck）来调节T细胞活化，并且PTP-PEST的下调可能是先前活化的T细胞对TCR触发的反应增加的原因。(C)2008爱思唯尔有限公司保留所有权利。
We report that the protein tyrosine phosphatase PTP-PEST is expressed in resting human and mouse CD4(+) and CD8(+) T cells, but not in Jurkat T leukemia cells, and that PTP-PEST protein, but not mRNA, was dramatically downregulated in CD4(+) and CD8(+) primary human T cells upon T cell activation. This was also true in mouse CD4(+) T cells, but less striking in mouse CD8+ T cells. PTP-PEST reintroduced into jurkat at levels similar to those in primary human T cells, was a potent inhibitor of TCR-induced transactivation of reporter genes driven by NFAT/AP-1 and NF-kappa B elements and by the entire IL-2 gene promoter. Introduction of PTP-PEST into previously activated primary human T cells also reduced subsequent IL-2 production by these cells in response to TCR and CD28 stimulation. The inhibitory effect of PTP-PEST was associated with dephosphorylation the Lck kinase at its activation loop site (Y394), reduced early TCR-induced tyrosine phosphorylation, reduced ZAP-70 phosphorylation and inhibition of MAP kinase activation. We propose that PTP-PEST tempers T cell activation by dephosphorylating TCR-proximal signaling molecules, such as Lck, and that down-regulation of PTP-PEST may be a reason for the increased response to TCR triggering of previously activated T cells. (C) 2008 Elsevier Ltd. All rights reserved.