Regulated cell death is essential for the maintenance of cellular and tissue homeostasis. In the hematopoietic system, genetic defects in apoptotic cell death generally produce the accumulation of immune cells, inflammation and autoimmunity. In contrast, we found that genetic deletion of caspases of the mitochondrial apoptosis pathway reduces natural killer (NK) cell numbers and makes NK cells functionally defective in vivo and in vitro. Caspase deficiency results in constitutive activation of a type I interferon (IFN) response, due to leakage of mitochondrial DNA and activation of the cGAS/STING pathway. The NK cell defect in caspase-deficient mice is independent of the type I IFN response, but the phenotype is partially rescued by cGAS or STING deficiency. Finally, caspase deficiency alters NK cells in a cell-extrinsic manner. Type I IFNs and NK cells are two essential effectors of antiviral immunity, and our results demonstrate that they are both regulated in a caspase-dependent manner. Beyond caspase-deficient animals, our observations may have implications in infections that trigger mitochondrial stress and caspase-dependent cell death.

中文翻译：

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促凋亡半胱天冬酶缺乏揭示了 NK 细胞调节的细胞外在机制

受调控的细胞死亡对于维持细胞和组织稳态至关重要。在造血系统中，凋亡细胞死亡的遗传缺陷通常会产生免疫细胞的积累、炎症和自身免疫。相比之下，我们发现线粒体凋亡途径的半胱天冬酶的基因缺失减少了自然杀伤 (NK) 细胞的数量，并使 NK 细胞在体内和体外出现功能缺陷. 由于线粒体 DNA 泄漏和 cGAS/STING 通路激活，半胱天冬酶缺乏导致 I 型干扰素 (IFN) 反应的组成型激活。caspase 缺陷小鼠中的 NK 细胞缺陷与 I 型 IFN 反应无关，但该表型可通过 cGAS 或 STING 缺陷部分挽救。最后，半胱天冬酶缺乏以细胞外在方式改变 NK 细胞。I 型 IFN 和 NK 细胞是抗病毒免疫的两个重要效应物，我们的结果表明它们都以半胱天冬酶依赖性方式受到调节。除了缺乏半胱天冬酶的动物，我们的观察可能对引发线粒体应激和半胱天冬酶依赖性细胞死亡的感染有影响。