Partially phosphorylated T cell receptor zeta molecules can inhibit T cell activation.
Partially phosphorylated T cell receptor zeta molecules can inhibit T cell activation.
复制标题
部分磷酸化的T细胞受体Zeta分子可以抑制T细胞活化。
DOI：
10.1084/jem.190.11.1627
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发表时间：
1999-12-06
期刊：
影响因子：
--
通讯作者：
Allen PM
中科院分区：
文献类型：
--
作者：
Kersh EN;Kersh GJ;Allen PM
T细胞受体复合物（TCR）β链在静息外周T细胞中的六个基于β免疫受体酪氨酸的激活基序（ITAM）酪氨酸残基中的两个处特异性地组成性酪氨酸磷酸化。TCR的激动剂和拮抗剂配体均诱导TCR1的进一步磷酸化，其中激动剂诱导TCR1酪氨酸的完全磷酸化。拮抗剂刺激后，ITAM磷酸化不完全，并产生离散形式的部分磷酸化ITAM。在这里，我们突变嵌合的人CD8-CD8受体分子中的特异性酪氨酸，以反映静息T细胞中的磷酸化以及激动剂和拮抗剂配体诱导的磷酸化。我们证明了这种部分磷酸化的TCR-γ种类可以抑制T细胞杂交瘤中IL-2的产生和T细胞克隆中的增殖。这揭示了部分磷酸化ITAM的先前未被识别的抑制功能。这些发现支持了TCR拮抗作用可以通过TCR复合物内抑制信号的产生而产生的概念，并且静息T细胞中的组成性磷酸化是抑制性信号传导环境。
The T cell receptor complex (TCR) ζ chain is constitutively tyrosine phosphorylated specifically at two of the six ζ immunoreceptor tyrosine-based activation motif (ITAM) tyrosine residues in resting peripheral T cells. Further phosphorylation of ζ is induced by both agonist and antagonist ligands of the TCR, with agonists inducing complete phosphorylation of the ζ ITAM tyrosines. After antagonist stimulation, ζ phosphorylation is incomplete and generates discrete forms of partially phosphorylated ITAMs. Here, we mutate specific tyrosines in chimeric human CD8-ζ molecules to reflect phosphorylation in resting T cells as well as phosphorylation induced by agonist and antagonist ligands. We demonstrate that such partially phosphorylated TCR-ζ species can inhibit IL-2 production in T cell hybridomas and proliferation in T cell clones. This reveals a previously unrecognized, inhibitory function of partially phosphorylated ITAMs. These findings support the concept that TCR antagonism can arise through the generation of an inhibitory signal within the TCR complex and that constitutive ζ phosphorylation in resting T cells is an inhibitory signaling environment.