Department of Infectious Diseases, Integrative Virology, CIID, University Hospital Heidelberg, Heidelberg, Germany.
Hartmut Hoffmann-Berling International Graduate School of Molecular and Cellular Biology (HBIGS), Heidelberg, Germany.
Sci Immunol. 2019 Jan 4;4(31). doi: 10.1126/sciimmunol.aav1987.
T cell antigen receptor (TCR) signaling triggers selective cytokine expression to drive T cell proliferation and differentiation required for immune defense and surveillance. The nuclear signaling events responsible for specificity in cytokine gene expression upon T cell activation are largely unknown. Here, we uncover formation of a dynamic actin filament network in the nucleus that regulates cytokine expression for effector functions of CD4 T lymphocytes. TCR engagement triggers the rapid and transient formation of a nuclear actin filament network via nuclear Arp2/3 complex, induced by elevated nuclear Ca levels and regulated via N-Wasp and NIK. Specific interference with TCR-induced formation of nuclear actin filaments impairs production of effector cytokines and prevents generation of antigen-specific antibodies but does not interfere with immune synapse formation and cell proliferation. Ca-regulated actin polymerization in the nucleus allows CD4 T cells the rapid conversion of TCR signals into effector functions required for T cell help.
T 细胞抗原受体 (TCR) 信号触发选择性细胞因子表达，从而驱动 T 细胞增殖和分化，以实现免疫防御和监测。T 细胞激活时负责细胞因子基因表达特异性的核信号事件在很大程度上是未知的。在这里，我们发现了一种动态的核内肌动蛋白丝网络的形成，该网络调节 CD4 T 淋巴细胞效应功能的细胞因子表达。TCR 结合通过核 Arp2/3 复合物触发核内肌动蛋白丝网络的快速和瞬时形成，这是由核内 Ca 水平升高诱导的，并通过 N-Wasp 和 NIK 进行调节。特异性干扰 TCR 诱导的核内肌动蛋白丝形成会损害效应细胞因子的产生，并阻止抗原特异性抗体的产生，但不会干扰免疫突触形成和细胞增殖。核内 Ca 调节的肌动蛋白聚合使 CD4 T 细胞能够快速将 TCR 信号转化为 T 细胞辅助所需的效应功能。
