Department of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, CO 80045.
Department of Pathology, University of Massachusetts Medical School, Worcester, MA 01605.
J Immunol. 2020 Jul 15;205(2):335-345. doi: 10.4049/jimmunol.1900853. Epub 2020 Jun 3.
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 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 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.
T 细胞受体信号强度对于抗原刺激后 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这个过程的幅度。连接分级 TCR 信号与产生不同数量的 IRF4 的信号机制尚未得到很好的理解。在这项研究中，我们表明抗原效价调节了单个小鼠 CD8 T 细胞中 NFAT1 激活的动力学但不调节其幅度。因此，传递较弱 TCR 信号的 T 细胞在 mRNA 诱导方面表现出明显的延迟，导致单个细胞中整体 IRF4 表达降低，克隆群体内异质性增加。我们进一步表明，酪氨酸激酶 ITK 的活性充当信号催化剂，可加速细胞对 TCR 刺激的反应速度，控制基因转录开始的时间。这些发现提供了对 ITK 在 TCR 信号转导中的功能的深入了解，该功能最终调节了对 TCR 信号强度变化的 IRF4 表达水平。
