NK细胞是重要的效应细胞，在对抗病原体方面起着重要的作用，并对肿瘤细胞具有强大的细胞溶解活性。一系列表面受体精细调节它们的功能和抑制性检查点，如PD-1，可以抑制免疫应答，诱导免疫抑制状态。事实上，人类NK细胞中的PD-1表达与效应细胞功能受损和肿瘤免疫逃避相关。重要的是，已经证明阻断PD-1/PD-L1轴可以逆转NK细胞疲劳，并增加它们的细胞毒性。最近，检查点受体的可溶性配体，如可溶性PD-1（sPD-1），因其生物活性和调控免疫应答的能力而引起高度关注。广泛的研究表明，sPD-1能够调节T细胞效应细胞功能并抑制肿瘤生长。肿瘤浸润的T细胞被认为是循环sPD-1的主要来源。此外，最近还证明，刺激的巨噬细胞也能释放sPD-1。然而，目前还没有关于sPD-1在其他先天免疫细胞亚群环境中的作用的数据，因此本研究旨在揭示sPD-1对人类NK细胞功能的影响。我们制备了重组sPD-1蛋白，并证明其与PD-L1结合，在其存在下可以增加NK细胞的细胞毒性。值得注意的是，我们还确定了调节内源性sPD-1在人类NK细胞中合成和释放的途径。分泌的内源性sPD-1保持其生物学功能，并能调节NK细胞的效应细胞功能。总的来说，这些数据揭示了sPD-1在调节NK介导的先天免疫反应中的关键作用。 版权所有 © 2023 Mariotti, Ingegnere, Landolina, Vacca, Munari, Moretta。

NK cells represent important effectors that play a major role in innate defences against pathogens and display potent cytolytic activity against tumor cells. An array of surface receptors finely regulate their function and inhibitory checkpoints, such as PD-1, can dampen the immune response inducing an immunosuppressive state. Indeed, PD-1 expression in human NK cells correlated with impaired effector function and tumor immune evasion. Importantly, blockade of the PD-1/PD-L1 axis has been shown to reverse NK cell exhaustion and increase their cytotoxicity. Recently, soluble counterparts of checkpoint receptors, such as soluble PD-1 (sPD-1), are rising high interest due to their biological activity and ability to modulate immune responses. It has been widely demonstrated that sPD-1 can modulate T cell effector functions and tumor growth. Tumor-infiltrating T cells are considered the main source of circulating sPD-1. In addition, recently, also stimulated macrophages have been demonstrated to release sPD-1. However, no data are present on the role of sPD-1 in the context of other innate immune cell subsets and therefore this study is aimed to unveil the effect of sPD-1 on human NK cell function. We produced the recombinant sPD-1 protein and demonstrated that it binds PD-L1 and that its presence results in increased NK cell cytotoxicity. Notably, we also identified a pathway regulating endogenous sPD-1 synthesis and release in human NK cells. Secreted endogenous sPD-1, retained its biological function and could modulate NK cell effector function. Overall, these data reveal a pivotal role of sPD-1 in regulating NK-mediated innate immune responses.Copyright © 2023 Mariotti, Ingegnere, Landolina, Vacca, Munari and Moretta.