Carcinoembryonic antigen-related cell adhesion molecule 1 inhibits proximal TCR signaling by targeting ZAP-70
Carcinoembryonic antigen-related cell adhesion molecule 1 inhibits proximal TCR signaling by targeting ZAP-70
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DOI：
10.4049/jimmunol.180.9.6085
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发表时间：
2008-05-01
影响因子：
4.4
通讯作者：
Blumberg, Richard S.
中科院分区：
文献类型：
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作者：
Chen, Zhangguo;Chen, Lanfen;Blumberg, Richard S.
癌胚抗原相关细胞粘附分子1（CEACAM 1）的长胞质尾（CT）异构体在活化的人T细胞上表达，并在CT中具有两个ITIM基序。CEACAM 1的这些同种型抑制由TCR/CD 3复合物引发的T细胞应答，抑制依赖于CEACAM 1和含Src同源2结构域的磷酸酶1（SHP-1）的ITIM。然而，这种抑制在T细胞中发生的机制尚不清楚。我们在这里证明，Src家族激酶，Lck，CEACAM 1的ITIM磷酸化是CEACAM 1与SHP-L结合的先决条件。我们进一步表明，CEACAM 1与SHP-1结合并将SHP-1募集到TCR/CD 3复合物，导致CD 3-zeta和ZAP-1的磷酸化降低。70，并因此降低了ZAP-70下游元件的活化。这在生理学上是相关的，因为使用特异性识别人CEACAM 1的嗜同性结合区的Fab消除SHP-1表达或阻断CEACAM 1的嗜同性结合增加了由TCR/CD 3复合物引发的细胞溶解功能。这些研究表明，CEACAM 1的长CT同种型通过集中于ZAP-70的活化来协调抑制程序，该抑制程序消除TCR/CD 3复合物下游的极近端事件。
The long cytoplasmic tail (CT) isoforms of carcinoembryonic Ag-related cell adhesion molecule 1 (CEACAM1) are expressed on activated human T cells and possess two ITIM motifs in the CT. These isoforms of CEACAM1 are inhibitory for T cell responses initiated by the TCR/CD3 complex with the inhibition dependent upon the ITIMs of CEACAM1 and Src homology 2 domain-containing phosphatase 1 (SHP-1). However, the mechanism by which this inhibition occurs in T cells is unknown. We demonstrate here that the Src family kinase, Lck, and the ability of CEACAM1 to bind homophilically are required for the ITIM phosphorylation of CEACAM1 that is a prerequisite for CEACAM1 association with SHP-L We further show that CEACAM1 associates with and recruits SHP-1 to the TCR/CD3 complex leading to decreased phosphorylation of CD3-zeta and ZAP-70 and consequently decreased activation of the elements downstream of ZAP-70. This is physiologically relevant because extinction of SHP-1 expression or blockade of homophilic binding by CEACAM1 using a Fab that specifically recognizes the homophilic binding region of human CEACAM1 increases the cytolytic function initiated by the TCR/CD3 complex. These studies show that long CT isoforms of CEACAM1 orchestrate an inhibitory program that abrogates extremely proximal events downstream of the TCR/CD3 complex by focusing on the activation of ZAP-70.