SHP-1 and SHP-2 associate with immunoreceptor tyrosine-based switch motif of programmed death 1 upon primary human T cell stimulation, but only receptor ligation prevents T cell activation
SHP-1 and SHP-2 associate with immunoreceptor tyrosine-based switch motif of programmed death 1 upon primary human T cell stimulation, but only receptor ligation prevents T cell activation
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DOI：
10.4049/jimmunol.173.2.945
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发表时间：
2004-07-15
影响因子：
4.4
通讯作者：
Riley, JL
中科院分区：
文献类型：
--
作者：
Chemnitz, JM;Parry, RV;Riley, JL
为了研究介导原代人CD4 T细胞中介导编程死亡I（PD-1）信号传导的顺式作用因子，我们构建了一个由鼠CD28细胞外域和人类PD-1细胞质尾部组成的嵌合分子。当引入CD4 T细胞中时，该构造模仿了内源性PD-1的活性，以抑制T细胞扩张和细胞因子产生的能力。 PD-1的细胞质尾巴包含两个结构基序，一个ITIM和一个免疫受体。基于酪氨酸的开关图案（ITSM）。 ITIM的突变对PD-1信号传导或功能活性几乎没有影响。相反，ITS的突变消除了PD-1阻断细胞因子合成和限制T细胞膨胀的能力。进一步的生化分析表明，PD-1阻断T细胞激活的能力与含有域含区域的磷酸磷酸酶-1（SHP-1）和SHP-2的募集相关的能力与适配器SRC同源性2域含有域的磷酸酶-1（SHP-1）和SHP-2相关。分子1a，到ITSM域。在TCR刺激的T细胞中，即使没有PD-1参与度，SHP-2与PD-1相关。尽管这种相互作用，PD-1可以阻止T细胞激活所需的受体连接的能力，这表明PD-1与CD3和/或CD28的共定位对于抑制T细胞激活可能是必需的。
To study the cis- and trans-acting factors that mediate programmed death I (PD-1) signaling in primary human CD4 T cells, we constructed a chimeric molecule consisting of the murine CD28 extracellular domain and human PD-1 cytoplasmic tail. When introduced into CD4 T cells, this construct mimics the activity of endogenous PD-1 in terms of its ability to suppress T cell expansion and cytokine production. The cytoplasmic tail of PD-1 contains two structural motifs, an ITIM and an immunoreceptor. tyrosine-based switch motif (ITSM). Mutation of the ITIM had little effect on PD-1 signaling or functional activity. In contrast, mutation of the ITSM abrogated the ability of PD-1 to block cytokine synthesis and to limit T cell expansion. Further biochemical analyses revealed that the ability of PD-1 to block T cell activation correlated with recruitment of Src homology region 2 domain-containing phosphatase-1 (SHP-1) and SHP-2, and not the adaptor Src homology 2 domain-containing molecule 1A, to the ITSM domain. In TCR-stimulated T cells, SHP-2 associated with PD-1, even in the absence of PD-1 engagement. Despite this interaction, the ability of PD-1 to block T cell activation required receptor ligation, suggesting that colocalization of PD-1 with CD3 and/or CD28 may be necessary for inhibition of T cell activation.