Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
Sir William Dunn School of Pathology, University of Oxford, Oxford, UK.
Eur J Immunol. 2016 Sep;46(9):2091-4. doi: 10.1002/eji.201646582.
Thymocyte development and maintenance of peripheral T-cell numbers and functions are critically dependent on T-cell receptor (TCR) signal strength. SHP1 (Src homology region 2 domain-containing phosphatase-1), a tyrosine phosphatase, acts as a negative regulator of TCR signal strength. Moreover, germline SHP1 knockout mice have shown impaired thymic development. However, this has been recently questioned by an analysis of SHP1 conditional knockout mice, which reported normal thymic development of SHP1 deficient thymocytes. Using this SHP1 conditional knockout mice, in this issue of the European Journal of Immunology, Martinez et al. [Eur. J. Immunol. 2016. 46: 2103-2110] show that SHP1 indeed does have a role in the negative regulation of TCR signal strength in positively selected thymocytes, and in the final maturation of single positive thymocytes. They report that thymocyte development in such mice shows loss of mature, post-selection cells. This is due to increased TCR signal transduction in thymocytes immediately post positive-selection, and increased cell death in response to weak TCR ligands. Thus, SHP1-deficiency shows strong similarities to deficiency in the T-cell specific SHP1-associated protein Themis.
胸腺细胞的发育以及外周 T 细胞数量和功能的维持，严重依赖于 T 细胞受体 (TCR) 信号强度。SHP1（Src 同源区 2 域含磷酸酶-1）是一种酪氨酸磷酸酶，作为 TCR 信号强度的负调节剂起作用。此外，胚系 SHP1 敲除小鼠表现出胸腺发育受损。然而，最近对 SHP1 条件性敲除小鼠的分析对此提出了质疑，该分析报告称 SHP1 缺陷的胸腺细胞的胸腺发育正常。在本期《欧洲免疫学杂志》中，Martinez 等人使用这种 SHP1 条件性敲除小鼠[Eur. J. Immunol. 2016. 46: 2103-2110]表明 SHP1 确实在正选择的胸腺细胞中的 TCR 信号强度的负调节以及单阳性胸腺细胞的最终成熟中发挥作用。他们报告说，这些小鼠的胸腺细胞发育表现出成熟后选择细胞的缺失。这是由于阳性选择后，胸腺细胞中的 TCR 信号转导增加，以及对弱 TCR 配体的细胞死亡增加。因此，SHP1 缺陷与 T 细胞特异性 SHP1 相关蛋白 Themis 的缺陷具有很强的相似性。
