Department of Medicine, University of Tennessee Health Science Center, Memphis, TN 38163, United States.
Department of Medicine, University of Tennessee Health Science Center, Memphis, TN 38163, United States; Microbiology-Immunology-Biochemistry, University of Tennessee Health Science Center, Memphis, TN 38163, United States; Research Service, Veterans Affairs Medical Center, Memphis, TN 38104, United States.
Clin Immunol. 2018 Jul;192:50-57. doi: 10.1016/j.clim.2018.04.007. Epub 2018 Apr 16.
The aim of this study was to understand how Syk affects peripheral T cell function. T cells from Syk chimeric mice and DR1 Syk CD4 conditional mice gave strong CD3-induced Th1, Th2, and Th17 cytokine responses. However, an altered peptide ligand (APL) of human CII (256-276) with two substitutions (F263N, E266D), also called A12, elicited only Th2 cytokine responses from Syk T cells but not SykCD4 T cells. Western blots revealed a marked increase in the phosphorylation of Syk, JNK and p38 upon A12/DR1 activation in WT or Syk T cells but not in SykCD4 cells. We demonstrate that Syk is required for the APL- induction of suppressive cytokines. Chemical Syk inhibitors blocked activation of GATA-3 by peptide A12/DR1. In conclusion, this study provides novel insights into the role that Syk plays in directing T cell activity, and may shape therapeutic approaches for autoimmune diseases.
本研究旨在了解 Syk 如何影响外周 T 细胞功能。Syk 嵌合小鼠和 DR1 Syk CD4 条件性敲除小鼠的 T 细胞产生了强烈的 CD3 诱导的 Th1、Th2 和 Th17 细胞因子反应。然而，一种人 CII（256-276）的变构肽配体（APL），具有两个取代（F263N、E266D），也称为 A12，仅从 Syk T 细胞而非 SykCD4 T 细胞中诱导出 Th2 细胞因子反应。Western blot 显示，在 WT 或 Syk T 细胞中，A12/DR1 激活后，Syk、JNK 和 p38 的磷酸化明显增加，但在 SykCD4 细胞中则没有。我们证明 Syk 是 APL 诱导抑制性细胞因子所必需的。化学 Syk 抑制剂阻断了肽 A12/DR1 对 GATA-3 的激活。总之，本研究为 Syk 在指导 T 细胞活性方面的作用提供了新的见解，并可能为自身免疫性疾病的治疗方法提供指导。
