Key Points T cell signals trigger activation of multiple events in the teleost Ca2+–NFAT axis. Tight regulation of Ca2+–NFAT is pivotal for teleost T cell activation and function. Ca2+–NFAT is a primitive regulatory strategy that emerged in teleost T cells. Calcium ion (Ca2+) is a widespread and primitive second messenger that regulates physiological cell functions in almost all life beings. Ca2+ influx-induced NFAT activation is essential for T cell function and adaptive immunity. However, whether and how Ca2+ signaling modulates T cell immunity in early vertebrates, especially in nontetrapods, remains largely unknown. To address these questions, a Nile tilapia (Oreochromis niloticus) model was employed to investigate the regulation of ancestral T cell immunity by Ca2+–NFAT signaling in jawed fish. In Nile tilapia, an evolutionarily conserved Ca2+–NFAT signaling pathway is involved in the primary adaptive immune response during Streptococcus agalactiae infection. Meanwhile, T cell signals trigger several events along the Ca2+–NFAT axis in this early vertebrate, including Ca2+ influx, calcineurin activation, and NFAT nuclear import. More critically, suppression of Ca2+–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 Ca2+–NFAT signaling on T cell immunity in a nontetrapod species. We suggest that modulation of T cell immunity by Ca2+–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.

中文翻译：

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Ca2+–钙调神经磷酸酶轴控制的 NFAT 核易位对于早期脊椎动物的最佳 T 细胞免疫至关重要

关键点 T 细胞信号触发硬骨鱼 Ca2+–NFAT 轴中多个事件的激活。Ca2+–NFAT 的严格调控是硬骨 T 细胞激活和功能的关键。Ca2+–NFAT 是一种原始的调节策略，出现在硬骨 T 细胞中。钙离子 (Ca2+) 是一种广泛存在的原始第二信使，几乎可以调节所有生物的生理细胞功能。Ca2+ 流入诱导的 NFAT 激活对于 T 细胞功能和适应性免疫至关重要。然而，Ca2+ 信号是否以及如何调节早期脊椎动物，尤其是非四足动物的 T 细胞免疫，在很大程度上仍然未知。为了解决这些问题，采用尼罗罗非鱼（Oreochromis niloticus）模型来研究下颌鱼中 Ca2+–NFAT 信号传导对祖先 T 细胞免疫的调节。在尼罗罗非鱼中，进化上保守的 Ca2+–NFAT 信号通路参与了无乳链球菌感染期间的初级适应性免疫反应。同时，T 细胞信号沿 Ca2+–NFAT 轴在这种早期脊椎动物中触发了几个事件，包括 Ca2+ 流入、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菌素 A 抑制 Ca2+–NFAT 信号会损害原始 T 细胞活化、克隆扩增和感染清除。从机制上讲，尼罗罗非鱼 NFAT 与其他几种转录因子相互作用以实现有效的基因表达，这种非四足动物中的 T 细胞分别使用 Cabin1 和 DYRK1A 来调节 NFAT 核输入和输出。据我们所知，该研究首次证明了 Ca2+–NFAT 信号传导对非四足动物 T 细胞免疫的调节机制。我们认为通过 Ca2+-NFAT 信号调节 T 细胞免疫是一种原始策略，在硬骨鱼从四足动物谱系分化之前就已经存在。这项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观点。