Repression of Hedgehog signal transduction in T-lineage cells increases TCR-induced activation and proliferation
Repression of Hedgehog signal transduction in T-lineage cells increases TCR-induced activation and proliferation
复制标题
T 谱系细胞中 Hedgehog 信号转导的抑制可增加 TCR 诱导的激活和增殖
作者：
N. Rowbotham;A. Furmanski;A. L. Hager;S. Ross;E. Drakopoulou;C. Koufaris;S. Outram;T. Crompton
Hedgehog蛋白信号的分化，存活和增殖的最早的胸腺祖细胞，但其功能在胸腺细胞发育的后期阶段和外周T细胞功能是有争议的。在这里，我们表明，通过表达Gli2的转基因阻遏物形式（Gli2δC2），抑制T细胞系细胞中的Hedgehog（Hh）途径活化，增加了T细胞分化和响应TCR信号传导的活化。Gli2δC2转基因的表达增加了从CD4+CD8+到单阳性胸腺细胞的分化，并增加了外周T细胞群。Gli2δC2 T细胞对通过连接CD3和CD28的活化具有高响应性：它们更快地表达细胞表面活化标记物CD69和CD25，并且比野生型T细胞增殖更多。这些数据显示胸腺细胞和T细胞中的Hedgehog途径活化负调节TCR依赖性分化和增殖。因此，作为TCR依赖性事件的负调节因子，Hh蛋白提供了对T细胞命运的环境影响。
Hedgehog proteins signal for differentiation, survival and proliferation of the earliest thymocyte progenitors, but their functions at later stages of thymocyte development and in peripheral T-cell function are controversial. Here we show that repression of Hedgehog (Hh) pathway activation in T-lineage cells, by expression of a transgenic repressor form of Gli2 (Gli2δC2), increased T-cell differentiation and activation in response to TCR signalling. Expression of the Gli2δC2 transgene increased differentiation from CD4+CD8+ to single positive thymocyte, and increased peripheral T cell populations. Gli2δC2 T-cells were hyper-responsive to activation by ligation of CD3 and CD28: they expressed cell surface activation markers CD69 and CD25 more quickly, and proliferated more than wild-type T-cells. These data show that Hedgehog pathway activation in thymocytes and T-cells negatively regulates TCR-dependent differentiation and proliferation. Thus, as negative regulators of TCR-dependent events, Hh proteins provide an environmental influence on T-cell fate.