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Activation of the Tec Kinase ITK Controls Graded IRF4 Expression in Response to Variations in TCR Signal Strength
The Journal of Immunology ( IF 4.4 ) Pub Date : 2020-06-03 , DOI: 10.4049/jimmunol.1900853
James M Conley 1 , Michael P Gallagher 2 , Anjana Rao 3, 4 , Leslie J Berg 2, 5
Affiliation  

Key Points Ag potency and ITK control graded IRF4 expression. Altered kinetics of NFAT activation provide a mechanism linking ITK and IRF4. TCR signal strength is critical for CD8+ T cell clonal expansion after Ag stimulation. Levels of the transcription factor IRF4 control the magnitude of this process through the induction of genes involved in proliferation and glycolytic metabolism. The signaling mechanism connecting graded TCR signaling to the generation of varying amounts of IRF4 is not well understood. In this study, we show that Ag potency regulates the kinetics but not the magnitude of NFAT1 activation in single mouse CD8+ T cells. Consequently, T cells that transduce weaker TCR signals exhibit a marked delay in Irf4 mRNA induction, resulting in decreased overall IRF4 expression in individual cells and increased heterogeneity within the clonal population. We further show that the activity of the tyrosine kinase ITK acts as a signaling catalyst that accelerates the rate of the cellular response to TCR stimulation, controlling the time to onset of Irf4 gene transcription. These findings provide insight into the function of ITK in TCR signal transduction that ultimately regulates IRF4 expression levels in response to variations in TCR signal strength.

中文翻译:

Tec 激酶 ITK 的激活控制分级 IRF4 表达以响应 TCR 信号强度的变化

关键点 Ag 效力和 ITK 控制分级 IRF4 表达。NFAT 激活动力学的改变提供了一种将 ITK 和 IRF4 联系起来的机制。TCR 信号强度对于 Ag 刺激后的 CD8+ T 细胞克隆扩增至关重要。转录因子 IRF4 的水平通过诱导参与增殖和糖酵解代谢的基因来控制该过程的大小。将分级 TCR 信号连接到不同数量的 IRF4 的信号机制尚不清楚。在这项研究中,我们表明 Ag 效力可调节动力学,但不能调节单个小鼠 CD8+ T 细胞中 NFAT1 激活的幅度。因此,转导较弱 TCR 信号的 T 细胞表现出 Irf4 mRNA 诱导的显着延迟,导致单个细胞中整体 IRF4 表达降低,并增加克隆群体内的异质性。我们进一步表明,酪氨酸激酶 ITK 的活性充当信号催化剂,加速细胞对 TCR 刺激的反应速率,控制 Irf4 基因转录开始的时间。这些发现让我们深入了解 ITK 在 TCR 信号转导中的功能,最终调节 IRF4 表达水平以响应 TCR 信号强度的变化。
更新日期:2020-06-03
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