Pharmacological inhibition of glycogen synthase kinase 3 regulates T cell development in vitro.
Pharmacological inhibition of glycogen synthase kinase 3 regulates T cell development in vitro.
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DOI：
10.1371/journal.pone.0058501
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Turner M
中科院分区：
文献类型：
--
作者：
Schroeder JH;Bell LS;Janas ML;Turner M
功能性T细胞的发育需要通过胸腺中的多个检查点的受体介导的转变。在称为β-选择的过程中，选择双阴性3（DN 3）胸腺细胞中重排的TCR β链的存在，该过程需要通过前TCR、Notch 1和CXCL 12进行信号传导。这些受体的信号整合集中在核心途径上，包括磷脂酰肌醇-3-激酶（PI 3 K）途径。糖原合成酶激酶3（GSK 3）通常被认为是由PI 3 K途径负调控，但其在β-选择中的作用尚未得到表征。在这里，我们表明，DN 3胸腺细胞的发育进程是促进GSK 3的合成化合物CHIR 99021抑制后。CHIR 99021允许在不存在前TCR-、Notch 1-或CXCL 12-介导的信号传导的情况下分化。它拮抗IL-7介导的DP胸腺细胞分化抑制，并增加IL-7促进的细胞恢复。这些数据表明在β-选择过程中GSK 3失活的潜在重要作用。它们可能有助于建立胸腺细胞发育的体外无基质细胞培养体系，并为筛选增殖、分化和凋亡调节因子提供新的平台。
The development of functional T cells requires receptor-mediated transition through multiple checkpoints in the thymus. Double negative 3 (DN3) thymocytes are selected for the presence of a rearranged TCR beta chain in a process termed β-selection which requires signalling via the pre-TCR, Notch1 and CXCL12. Signal integration by these receptors converges on core pathways including the Phosphatidylinositol–3-kinase (PI3K) pathway. Glycogen Synthase Kinase 3 (GSK3) is generally thought to be negatively regulated by the PI3K pathway but its role in β-selection has not been characterised. Here we show that developmental progression of DN3 thymocytes is promoted following inhibition of GSK3 by the synthetic compound CHIR99021. CHIR99021 allows differentiation in the absence of pre-TCR-, Notch1- or CXCL12-mediated signalling. It antagonizes IL-7-mediated inhibition of DP thymocyte differentiation and increases IL-7-promoted cell recovery. These data indicate a potentially important role for inactivation of GSK3 during β-selection. They might help to establish an in vitro stromal cell-free culture system of thymocyte development and offer a new platform for screening regulators of proliferation, differentiation and apoptosis.
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影响因子：
--
作者：
McKenzie G;Ward G;Stallwood Y;Briend E;Papadia S;Lennard A;Turner M;Champion B;Hardingham GE
通讯作者：
Hardingham GE
DOI：
10.3410/b2-82
发表时间：
2010-11-24
期刊：
F1000 biology reports
影响因子：
--
作者：
Voskas D;Ling LS;Woodgett JR
通讯作者：
Woodgett JR
影响因子：
4.4
作者：
Ciofani, M;Schmitt, TM;Zúñiga-Pflücker, JC
通讯作者：
Zúñiga-Pflücker, JC
影响因子：
4.4
作者：
Janas, Michelle L.;Turner, Martin
通讯作者：
Turner, Martin
影响因子：
30.5
作者：
Gounari, F;Aifantis, I;von Boehmer, H
通讯作者：
von Boehmer, H