TCR ligand discrimination is enforced by competing ERK positive and SHP-1 negative feedback pathways
TCR ligand discrimination is enforced by competing ERK positive and SHP-1 negative feedback pathways
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DOI：
10.1038/ni895
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发表时间：
2003-03-01
影响因子：
30.5
通讯作者：
Germain, RN
中科院分区：
文献类型：
--
作者：
Stefanová, I;Hemmer, B;Germain, RN
结构相似的自身抗原和外来抗原之间的功能区分是获得性免疫的一个主要属性。在这里，我们描述了T淋巴细胞中的两种反馈机制，它们共同加强和放大了与T细胞受体(TCR)参与质量相关的初始信号差异。弱结合的配体主要触发负反馈循环，导致酪氨酸磷酸酶SHP-1的快速募集，随后通过LCK激酶的失活而使受体脱敏。相反，强结合配体有效地激活了涉及ERK修饰LCK的正反馈电路，阻止了SHP-1的招募，并允许基因激活所需的长时间信号传递。这些途径的特征表明，它们构成了允许T细胞区分自身和外源配体的机制的重要组成部分。
Functional discrimination between structurally similar self and foreign antigens is a main attribute of adaptive immunity. Here we describe two feedback mechanisms in T lymphocytes that together sharpen and amplify initial signaling differences related to the quality of T cell receptor (TCR) engagement. Weakly binding ligands predominantly trigger a negative feedback loop leading to rapid recruitment of the tyrosine phosphatase SHP-1, followed by receptor desensitization through inactivation of Lck kinase. In contrast, strongly binding ligands efficiently activate a positive feedback circuit involving Lck modification by ERK, preventing SHP-1 recruitment and allowing the long-lasting signaling necessary for gene activation. The characteristics of these pathways suggest that they constitute an important part of the mechanism allowing T cells to discriminate between self and foreign ligands.