Program in Molecular Pathogenesis, Helen L. and Martin S. Kimmel Center for Biology and Medicine of the Skirball Institute of Biomolecular Medicine, New York, NY 10016, USA.
Immunity. 2010 Apr 23;32(4):531-40. doi: 10.1016/j.immuni.2010.04.005.
Agonist MHC-peptide complexes in the immunological synapse (IS) signal through T cell receptor (TCR) microclusters (MCs) that converge into a central supramolecular activation cluster (cSMAC). The determinants and function of the cSMAC remain unknown. We demonstrate an essential role for ubiquitin (Ub) and TSG101, but less so for HRS, in signal processing events at the cSMAC. Using siRNA in primary T cells, we show that Ub recognition by TSG101 is required for cSMAC formation, TCR MC signal termination, TCR downregulation, and segregation of TCR-MHC-peptide from PKC-theta-enriched signaling complexes. Weak agonist MHC-peptide induced CD80-dependent TCR MCs that dissociated in the center of the IS without recruiting TSG101. These results support TSG101-dependent recognition of CD80-independent TCR MCs as a molecular checkpoint for TCR downregulation.
免疫突触（IS）中的激动剂 MHC-肽复合物通过 T 细胞受体（TCR）微簇（MC）发出信号，这些 MC 汇聚成一个中央超分子激活簇（cSMAC）。cSMAC 的决定因素和功能尚不清楚。我们证明了泛素（Ub）和 TSG101 在 cSMAC 处的信号处理事件中起着重要作用，但 HRS 的作用则不那么重要。我们在原代 T 细胞中使用 siRNA 表明，TSG101 对 Ub 的识别对于 cSMAC 的形成、TCR MC 信号终止、TCR 下调以及 TCR-MHC-肽与富含 PKC-theta 的信号复合物的分离都是必需的。弱激动剂 MHC-肽诱导的 CD80 依赖性 TCR MC 在 IS 的中心解离，而没有招募 TSG101。这些结果支持 TSG101 依赖性识别 CD80 非依赖性 TCR MC 作为 TCR 下调的分子检查点。
