Dissociation of intracellular signaling pathways in response to partial agonist ligands of the T cell receptor
Dissociation of intracellular signaling pathways in response to partial agonist ligands of the T cell receptor
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DOI：
10.1084/jem.187.10.1699
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发表时间：
1998-05-18
影响因子：
15.3
通讯作者：
Madrenas, J
中科院分区：
文献类型：
--
作者：
Chau, LA;Bluestone, JA;Madrenas, J
T细胞受体（TCR）是一种多功能受体，能够产生不同的信号，导致不同的T细胞反应。早期信号的模式由TCR结合动力学决定，所述TCR结合动力学控制配体与TCR和辅助受体共接合的能力。TCR和CD 4的共接合导致具有TCR亚基的完全酪氨酸磷酸化以及ZAP-70的募集和活化的激动剂信号传导模式。相比之下，没有CD 4共接合的TCR接合引起部分激动剂类型的信号传导，其特征在于TCR亚基的不同磷酸化和募集，但没有ZAP-70的活化。由部分激动剂信号传导触发的途径是未知的。在这里，我们表明，激动剂导致协会的积极lck和积极ZAP-70与p120-GTP酶激活蛋白（p120-GAP）。这些关联分别遵循CD 4或CD 3的参与。相反，部分激动剂不激活lck或ZAP-70，但诱导p120-GAP与无活性ZAP-70的缔合。尽管存在这些差异，激动剂和部分激动剂信号都激活丝裂原活化蛋白激酶（MAPK）途径。然而，部分激动剂对MAPK的激活是短暂的，这支持了TCR配体变体作用机制的动力学、CD 4依赖性模型。瞬时MAPK激活可以解释对TCR部分激动剂和拮抗剂的一些反应。
The T cell receptor (TCR) is a versatile receptor able to generate different signals that result in distinct T cell responses. The pattern of early signals is determined by the TCR binding kinetics that control the ability of the ligand to coengage TCR and coreceptor. Coengagement of TCR and CD4 results in an agonist signaling pattern with complete tyrosine phosphorylation of TCR subunits, and recruitment and activation of ZAP-70. In contrast, TCR engagement without CD4 coengagement causes a partial agonist type of signaling, characterized by distinct phosphorylation of TCR subunits and recruitment but no activation of ZAP-70. The pathways triggered by partial agonist signaling are unknown. Here, we show that agonists cause association of active lck and active ZAP-70 with p120-GTPase-activating protein (p120-GAP). These associations follow engagement of CD4 or CD3, respectively. In contrast, partial agonists do not activate lck or ZAP-70, but induce association of p120-GAP with inactive ZAP-70. Despite these differences, both agonist and partial agonist signals activate the mitogen-activated protein kinase (MAPK) pathway. However, MAPK activation by partial agonists is transient, supporting a kinetic, CD4-dependent model for the mechanism of action of variant TCR ligands. Transient MAPK activation may explain some of the responses to TCR partial agonists and antagonists.