State Key Laboratory of Estuarine and Coastal Research, School of Life Sciences, East China Normal University, Shanghai 200241, China; and.
State Key Laboratory of Estuarine and Coastal Research, School of Life Sciences, East China Normal University, Shanghai 200241, China; and
J Immunol. 2020 Feb 1;204(3):569-585. doi: 10.4049/jimmunol.1901065. Epub 2019 Dec 23.
Calcium ion (Ca) is a widespread and primitive second messenger that regulates physiological cell functions in almost all life beings. Ca influx-induced NFAT activation is essential for T cell function and adaptive immunity. However, whether and how Ca signaling modulates T cell immunity in early vertebrates, especially in nontetrapods, remains largely unknown. To address these questions, a Nile tilapia () model was employed to investigate the regulation of ancestral T cell immunity by Ca-NFAT signaling in jawed fish. In Nile tilapia, an evolutionarily conserved Ca-NFAT signaling pathway is involved in the primary adaptive immune response during infection. Meanwhile, T cell signals trigger several events along the Ca-NFAT axis in this early vertebrate, including Ca influx, calcineurin activation, and NFAT nuclear import. More critically, suppression of Ca-NFAT signaling by the calcineurin inhibitor cyclosporine A impairs primordial T cell activation, clonal expansion, and infection clearance. Mechanistically, Nile tilapia NFAT interacts with several other transcription factors for potent gene expression, and T cells in this nontetrapod employ Cabin1 and DYRK1A to regulate NFAT nuclear import and export, respectively. To the best of our knowledge, this study is the first to demonstrate the regulatory mechanism of Ca-NFAT signaling on T cell immunity in a nontetrapod species. We suggest that modulation of T cell immunity by Ca-NFAT signaling is a primitive strategy that already existed prior to the divergence of bony fish from the tetrapod lineage. The findings of this study provide valuable perspectives for understanding the evolution of adaptive immune system.
钙离子（Ca）是一种广泛存在且原始的第二信使，调节着几乎所有生命形式的生理细胞功能。Ca 内流诱导的 NFAT 激活对于 T 细胞功能和适应性免疫至关重要。然而，Ca 信号是否以及如何调节早期脊椎动物（尤其是非四足动物）中的 T 细胞免疫仍知之甚少。为了解决这些问题，我们采用尼罗罗非鱼（）模型来研究 Ca-NFAT 信号在有颌鱼类中对祖细胞 T 细胞免疫的调控。在尼罗罗非鱼中，一条进化保守的 Ca-NFAT 信号通路参与了 感染期间的主要适应性免疫反应。同时，T 细胞信号在这种早期脊椎动物中沿着 Ca-NFAT 轴触发了几个事件，包括 Ca 内流、钙调神经磷酸酶激活和 NFAT 核输入。更重要的是，钙调神经磷酸酶抑制剂环孢素 A 抑制 Ca-NFAT 信号会损害原始 T 细胞的激活、克隆扩增和感染清除。从机制上讲，尼罗罗非鱼 NFAT 与其他几个转录因子相互作用，从而实现强有力的基因表达，并且这种非四足动物中的 T 细胞分别利用 Cabin1 和 DYRK1A 来调节 NFAT 的核输入和输出。据我们所知，这项研究首次证明了 Ca-NFAT 信号对非四足动物物种 T 细胞免疫的调控机制。我们认为，Ca-NFAT 信号对 T 细胞免疫的调节是一种原始策略，早在硬骨鱼类与四足动物谱系分化之前就已经存在。本研究的发现为理解适应性免疫系统的进化提供了有价值的视角。
