Kersh E N, Kersh G J, Allen P M
Center for Immunology and Department of Pathology, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
J Exp Med. 1999 Dec 6;190(11):1627-36. doi: 10.1084/jem.190.11.1627.
The T cell receptor complex (TCR) zeta chain is constitutively tyrosine phosphorylated specifically at two of the six zeta immunoreceptor tyrosine-based activation motif (ITAM) tyrosine residues in resting peripheral T cells. Further phosphorylation of zeta is induced by both agonist and antagonist ligands of the TCR, with agonists inducing complete phosphorylation of the zeta ITAM tyrosines. After antagonist stimulation, zeta phosphorylation is incomplete and generates discrete forms of partially phosphorylated ITAMs. Here, we mutate specific tyrosines in chimeric human CD8-zeta 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-zeta 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 zeta phosphorylation in resting T cells is an inhibitory signaling environment.
T细胞受体复合物（TCR）ζ链在静息外周T细胞中，其六个ζ免疫受体酪氨酸激活基序（ITAM）酪氨酸残基中的两个会持续发生特异性酪氨酸磷酸化。TCR的激动剂和拮抗剂配体均可诱导ζ链的进一步磷酸化，其中激动剂可诱导ζ链ITAM酪氨酸残基完全磷酸化。拮抗剂刺激后，ζ链磷酸化不完全，会产生部分磷酸化ITAM的不同形式。在此，我们对嵌合人CD8-ζ分子中的特定酪氨酸进行突变，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，这种部分磷酸化的TCR-ζ物种可抑制T细胞杂交瘤中的IL-2产生以及T细胞克隆中的增殖。这揭示了部分磷酸化ITAM此前未被认识到的抑制功能。这些发现支持了这样一种概念，即TCR拮抗作用可通过在TCR复合物内产生抑制信号而产生，并且静息T细胞中的ζ链组成性磷酸化是一种抑制性信号环境。
