Impaired activation and localization of LAT in anergic T cells as a consequence of a selective palmitoylation defect
Impaired activation and localization of LAT in anergic T cells as a consequence of a selective palmitoylation defect
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DOI：
10.1016/j.immuni.2006.03.011
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发表时间：
2006-05-01
期刊：
影响因子：
32.4
通讯作者：
Altman, Amnon
中科院分区：
文献类型：
--
作者：
Hundt, Matthias;Tabata, Hiroki;Altman, Amnon
T细胞无反应性的分子基础尚未完全了解。我们发现，在抗原致敏的无反应性小鼠CD 4（+）T细胞中，激活T细胞（LAT）的接头在CD 3/CD 28再刺激后低磷酸化。LAT下游的信号事件（PLC γ 1磷酸化和p85 [PI 3-K]结合）受损，而上游事件（CD 3 zeta和ZAP-70磷酸化）保持完整。LAT招募免疫突触和其本地化的洗涤剂抗性膜（DRM）部分是有缺陷的无能T细胞。这些缺陷由LAT的棕榈酰化受损引起，并且是选择性的，因为DRM定位和Fyn的棕榈酰化是完整的。该LAT缺陷独立于Cbl-b，并且不反映增强的LAT降解。这些结果确定LAT作为无反应诱导的最上游靶点;此外，它们表明通过翻译后棕榈酰化调节免疫突触和DRM中LAT的量有助于诱导T细胞无反应。
The molecular basis of T cell anergy is not completely understood. We show that in antigen-primed anergic murine CD4(+) T cells the linker for activation of T cells (LAT) is hypophosphorylated upon CD3/CD28 restimulation. Signaling events downstream of LAT (PLC gamma 1 phosphorylation and p85 [PI3-K] association) were impaired, whereas upstream events (CD3 zeta and ZAP-70 phosphorylation) remained intact. LAT recruitment to the immunological synapse and its localization in detergent-resistant membrane (DRM) fractions were defective in anergic T cells. These defects resulted from impaired palmitoylation of LAT and were selective since the DRM localization and palmitoylation of Fyn were intact. This LAT defect was independent of Cbl-b and did not reflect enhanced LAT degradation. These results identify LAT as the most upstream target of anergy induction; moreover, they suggest that regulation of the amount of LAT in the immunological synapse and DRM by posttranslational palmitoylation contributes to the induction of T cell anergy.