Partial signaling by CD8+ T cells in response to antagonist ligands.
Partial signaling by CD8+ T cells in response to antagonist ligands.
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DOI：
10.1084/jem.184.1.149
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发表时间：
1996-07-01
期刊：
影响因子：
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通讯作者：
Germain RN
中科院分区：
文献类型：
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作者：
Reis e Sousa C;Levine EH;Germain RN
激动肽-主要组织相容性复合体(MHC)分子配体的结构变体可以表现出部分激动剂和/或拮抗剂特性。许多这种改变的配体似乎是纯粹的拮抗剂。它们缺乏任何可检测到的诱导T细胞效应器功能的能力，并被描述为无法诱导钙瞬变和肌醇磷酸盐的周转。这被解释为这些配体不能启动任何依赖T细胞受体(TCR)的信号转导，它们的拮抗剂特性归因于与提供的激动剂竞争占据TCR。然而，成熟CD8+T细胞的拮抗剂可以诱导胸腺细胞的阳性选择，这意味着主动诱导T细胞分化事件，而部分激动剂或激动剂/拮抗剂组合诱导CD4+T细胞中TCR相关的早期酪氨酸磷酸化事件的独特模式。因此，我们直接研究了CD8+T细胞系中TCR信号对各种相关配体的反应。TCR与天然多肽-MHC I类激动剂的结合导致了与CD4+细胞相同的TCR相关的酪氨酸磷酸化事件，包括p21和p23形式的磷酸化Zeta的积聚，CD3 epsilon的磷酸化，以及磷酸化ZAP-70与TCR的结合。然而，两种缺乏诱导任何可检测到的CTL效应反应(细胞溶解、酯酶释放、干扰素分泌、白细胞介素2受体α上调)的拮抗剂也被发现也能诱导TCR依赖的磷酸化事件。在这些病例中，p21形式的磷酸化Zeta优先聚集，而不是CD3 epsilon的净磷酸化，以及非磷酸化的ZAP-70激酶与受体的联系。这些数据表明，不同的配体在CD8+T细胞中诱导类似于在CD4+细胞中首次观察到的TCR依赖的磷酸化事件。更重要的是，他们证明了一些假定的纯拮抗剂实际上是部分激动剂的子集，能够通过TCR诱导细胞内的生化变化。这种由拮抗剂传递的部分信号增加了这样一种可能性，即在某些情况下，拮抗作用可能是通过主动干扰激动剂对成熟T细胞中效应器活性的刺激而产生的，而相同的变异信号可以选择性地触发细胞内事件，从而允许胸腺细胞的阳性选择而不是消极选择。
Structural variants of an agonist peptide-major histocompatibility complex (MHC) molecule ligand can show partial agonist and/or antagonist properties. A number of such altered ligands appear to act as pure antagonists. They lack any detectable ability to induce T cell effector function and have been described as unable to induce calcium transients and turnover of inositol phosphates. This has been interpreted as an inability of these ligands to initiate any T cell receptor (TCR)-dependent signal transduction, with their antagonist properties ascribed to competition with offered agonist for TCR occupancy. Yet antagonists for mature CD8+ T cells can induce positive selection of thymocytes, implying active induction of T cell differentiation events, and partial agonists or agonist/antagonist combinations elicit a distinctive pattern of early TCR-associated tyrosine phosphorylation events in CD4+ T cells. We have therefore directly examined proximal TCR signaling in a CD8+ T cell line in response to various related ligands. TCR engagement with natural peptide-MHC class I agonist resulted in the same pattern of early TCR- associated tyrosine phosphorylation events as seen with CD4+ cells, including accumulation of both the p21 and p23 forms of phosphorylated zeta, phosphorylation of CD3 epsilon, and association of phosphorylated ZAP-70 with the TCR. Two antagonists that lacked the ability to induce any detectable CTL effector response (cytolysis, esterase release, gamma interferon secretion, interleukin-2 receptor alpha upregulation) were nevertheless found to also induce TCR-dependent phosphorylation events. In these cases, there was preferential accumulation of the p21 form of phospho-zeta without net phosphorylation of CD3 epsilon, as well as the association of nonphosphorylated ZAP-70 kinase with the receptor. These data show that variant ligands induce similar TCR- dependent phosphorylation events in CD8+ T cells as first observed in CD4+ cells. More importantly, they demonstrate that some putatively pure antagonists are actually a subset of partial agonists able to induce intracellular biochemical changes through the TCR. This delivery of a partial signal by antagonists raises the possibility that antagonism in some cases may result from active interference with stimulation of effector activity by agonist in mature T cells, while the same variant signal could selectively trigger intracellular events that allow positive without negative selection in thymocytes.