Differential T cell signaling induced by antagonist peptide-MHC complexes and the associated phenotypic responses.
Differential T cell signaling induced by antagonist peptide-MHC complexes and the associated phenotypic responses.
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DOI：
10.4049/jimmunol.158.5.2057
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发表时间：
1997-03
影响因子：
4.4
通讯作者：
D. La Face;C. Couture;K. Anderson;G. Shih;J. Alexander;A. Sette;T. Mustelin;A. Altman;H. Grey
中科院分区：
文献类型：
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作者：
D. La Face;C. Couture;K. Anderson;G. Shih;J. Alexander;A. Sette;T. Mustelin;A. Altman;H. Grey
TCR接触残基的某些变化已显示对肽Ag刺激T细胞应答的能力具有深远影响。尽管这些变化中的一些显然导致与TCR相互作用的能力的完全丧失，但其他变化导致部分激动剂活性（例如，无增殖的细胞因子产生）或拮抗剂活性（即，抑制Ag与TCR接合的能力）。我们发现MHC II类限制性拮抗剂活性与早期酪氨酸磷酸化事件的差异模式相关，其特征在于低分子量TCR ζ磷酸化的优势和Zap-70磷酸化的失败。这些早期酪氨酸磷酸化模式与先前描述的部分激动剂相同。因此，部分激动剂表型，如无反应性诱导不能归因于这种模式的酪氨酸磷酸化的因果关系。我们进一步扩展激动剂和拮抗剂肽引起的信号转导的研究，通过表征与TCRzeta亚型和p120原癌基因c-Cbl的差异磷酸化相关的Zap-70的差异募集。用拮抗剂肽研究了TCR与Ag接合后的另一个早期事件，即TCR的下调。我们表明，拮抗剂肽不引起TCR下调。这种失败可能代表拮抗剂抑制抗原介导的T细胞刺激的机制。
Certain changes in TCR contact residues have been shown to have profound effects on the capacity of a peptide Ag to stimulate a T cell response. Although some of these changes apparently lead to a complete loss of the ability to interact with the TCR, others result in partial agonist activity (e.g., cytokine production without proliferation) or antagonist activity (i.e., the capacity to inhibit the engagement to the TCR by Ag). We show MHC class II-restricted antagonist activity was associated with a differential pattern of early tyrosine phosphorylation events that was characterized by a preponderance of phosphorylation of low molecular mass TCRzeta and the failure to phosphorylate Zap-70. These early tyrosine phosphorylation patterns are the same as those previously described for partial agonists. Thus, a partial agonist phenotype such as anergy induction cannot be ascribed in a causal manner to this pattern of tyrosine phosphorylation. We further extend the studies of signal transduction elicited by agonist and antagonist peptides by characterizing differential recruitment of Zap-70 associated with TCRzeta isoforms and differential phosphorylation of p120 proto-oncogene c-Cbl. Another early event following TCR engagement by Ag, down-modulation of the TCR, was studied with antagonist peptides. We show that antagonist peptides do not cause TCR down-modulation. This failure may represent a mechanism by which antagonists inhibit antigen-mediated stimulation of T cells.