Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117545.
MOE Key Laboratory of Protein Sciences, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, School of Life Sciences, Institute for Immunology, Tsinghua University, Beijing 100084, China.
Proc Natl Acad Sci U S A. 2018 Nov 27;115(48):E11331-E11340. doi: 10.1073/pnas.1720209115. Epub 2018 Nov 9.
Thymocyte-expressed molecule involved in selection (Themis) has been shown to be important for T cell selection by setting the threshold for positive versus negative selection. Themis interacts with the protein tyrosine phosphatase (PTP) Src-homology domain containing phosphatase-1 (Shp1), a negative regulator of the T cell receptor (TCR) signaling cascade. However, how Themis regulates Shp1 is still not clear. Here, using a very sensitive phosphatase assay on ex vivo thymocytes, we have found that Themis enhances Shp1 phosphatase activity by increasing its phosphorylation. This positive regulation of Shp1 activity by Themis is found in thymocytes, but not in peripheral T cells. Shp1 activity is modulated by different affinity peptide MHC ligand binding in thymocytes. Themis is also associated with phosphatase activity, due to its constitutive interaction with Shp1. In the absence of Shp1 in thymocytes, Themis interacts with Shp2, which leads to almost normal thymic development in Shp1 conditional knockout (cKO) mice. Double deletion of both Themis and Shp1 leads to a thymic phenotype similar to that of Themis KO. These findings demonstrate unequivocally that Themis positively regulates Shp1 phosphatase activity in TCR-mediated signaling in developing thymocytes.
胸腺细胞表达的参与选择的分子（Themis）已被证明通过设定正选择与负选择的阈值对 T 细胞选择很重要。Themis 与蛋白酪氨酸磷酸酶（PTP）Src 同源结构域包含磷酸酶-1（Shp1）相互作用，后者是 T 细胞受体（TCR）信号级联的负调节剂。然而，Themis 如何调节 Shp1 尚不清楚。在这里，我们使用一种非常灵敏的磷酸酶测定法对体外胸腺细胞进行检测，发现 Themis 通过增加其磷酸化来增强 Shp1 磷酸酶活性。这种对 Shp1 活性的正调节作用仅在胸腺细胞中发现，而不在外周 T 细胞中发现。Shp1 活性通过不同亲和力肽 MHC 配体结合在胸腺细胞中进行调节。由于其与 Shp1 的组成性相互作用，Themis 也与磷酸酶活性相关。在胸腺细胞中缺乏 Shp1 的情况下，Themis 与 Shp2 相互作用，这导致 Shp1 条件性敲除（cKO）小鼠的胸腺发育几乎正常。Themis 和 Shp1 的双重缺失导致与 Themis KO 相似的胸腺表型。这些发现明确表明，Themis 在 TCR 介导的信号转导中正向调节发育中的胸腺细胞中的 Shp1 磷酸酶活性。
