Multiplex interrogation of the NK cell signalome reveals global downregulation of CD16 signaling during lentivirus infection through an IL-18/ADAM17-dependent mechanism.
Multiplex interrogation of the NK cell signalome reveals global downregulation of CD16 signaling during lentivirus infection through an IL-18/ADAM17-dependent mechanism.
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DOI：
10.1371/journal.ppat.1011629
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发表时间：
2023-09
期刊：
影响因子：
6.7
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中科院分区：
文献类型：
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尽管它们的重要性，自然杀伤（NK）细胞反应经常在人类免疫缺陷病毒-1（HIV-1）和猿猴免疫缺陷病毒（SIV）感染期间功能失调，即使不考虑抗逆转录病毒治疗，其潜在机制知之甚少。慢病毒感染中的NK细胞表面受体调节已被广泛研究，但对复杂细胞信号传导的更深入询问大多不存在，这主要是由于缺乏任何全面的NK细胞信号传导测定。为了填补这一知识空白，我们开发了一种新的多重信号传导分析，以广泛评估NK细胞信号传导。使用该测定，我们阐明了NK细胞在HIV-1（PLWH）感染者和SIV感染的恒河猴中均表现出来自CD 16的全局信号传导减少。有趣的是，抗逆转录病毒治疗不能完全恢复PLWH NK细胞中减少的CD 16信号传导。作为一种假定的机制，我们证明了NK细胞通过在HIV-1感染期间升高血浆IL-18水平来增加表面ADAM 17的表达，这反过来又减少了表面CD 16的下调。我们还表明，CD 16的表达和信号可以通过ADAM 17扰动恢复。总之，我们的多重NK细胞信号传导分析描绘了慢病毒感染特异性的独特NK细胞信号传导扰动，导致其功能障碍。我们的分析还提供了恢复失调的NK细胞功能的机制，为开发新的基于NK细胞的HIV-1疾病免疫治疗药物提供了潜在的见解。自然杀伤（NK）细胞对人类免疫缺陷病毒-1（HIV-1）和猿猴免疫缺陷病毒（SIV）感染发挥关键的先天效应反应，但在慢性慢病毒感染期间，其功能经常失调，机制尚不清楚。具体而言，与这种免疫功能障碍相关的NK细胞信号传导的影响尚未得到全面阐明。为了填补知识上的差距，我们开发了一种新的NK细胞多重信号传导试验，并将其应用于HIV-1感染者（PLWH）或SIV感染的恒河猴（RM）的NK细胞。我们说明了CD 16下游的信号传导激活，NK细胞功能的关键受体，在慢性慢病毒感染的NK细胞中全身下调，无论抗逆转录病毒治疗，这是由HIV-1/SIV感染引发的炎症反应介导的。总之，我们证明了全球CD 16信号下调NK细胞在HIV-1和SIV感染，使用我们的新的多重信号分析，并阐明了受损的NK细胞活性的推定机制。这些数据有利于进一步推进基于NK细胞的免疫治疗剂用于HIV-1治愈。
Despite their importance, natural killer (NK) cell responses are frequently dysfunctional during human immunodeficiency virus-1 (HIV-1) and simian immunodeficiency virus (SIV) infections, even irrespective of antiretroviral therapies, with poorly understood underlying mechanisms. NK cell surface receptor modulation in lentivirus infection has been extensively studied, but a deeper interrogation of complex cell signaling is mostly absent, largely due to the absence of any comprehensive NK cell signaling assay. To fill this knowledge gap, we developed a novel multiplex signaling analysis to broadly assess NK cell signaling. Using this assay, we elucidated that NK cells exhibit global signaling reduction from CD16 both in people living with HIV-1 (PLWH) and SIV-infected rhesus macaques. Intriguingly, antiretroviral treatment did not fully restore diminished CD16 signaling in NK cells from PLWH. As a putative mechanism, we demonstrated that NK cells increased surface ADAM17 expression via elevated plasma IL-18 levels during HIV-1 infection, which in turn reduced surface CD16 downregulation. We also illustrated that CD16 expression and signaling can be restored by ADAM17 perturbation. In summary, our multiplex NK cell signaling analysis delineated unique NK cell signaling perturbations specific to lentiviral infections, resulting in their dysfunction. Our analysis also provides mechanisms that will inform the restoration of dysregulated NK cell functions, offering potential insights for the development of new NK cell-based immunotherapeutics for HIV-1 disease. Natural killer (NK) cells exert critical innate effector responses against human immunodeficiency virus-1 (HIV-1) and simian immunodeficiency virus (SIV) infections, but their functions are often dysregulated during chronic lentiviral infection with understudied mechanisms. Specifically, the effect on NK cell signaling linked to this immune dysfunction has not been comprehensively elucidated. To fill the gap in knowledge, we developed a novel multiplex signaling assay for NK cells and applied it to NK cells from people living with HIV-1 (PLWH) or SIV-infected rhesus macaques (RM). We illustrated the signaling activation downstream of CD16, a critical receptor for NK cell function, is systemically downregulated in NK cells in chronic lentiviral infection regardless of antiretroviral treatment, which is mediated by inflammatory responses triggered by HIV-1/SIV infection. Taken together, we demonstrated global CD16 signaling downregulation in NK cells in HIV-1 and SIV infection using our novel multiplex signaling assay and elucidated the putative mechanism of impaired NK cell activities. These data are beneficial to further advance NK cell-based immunotherapeutics for an HIV-1 cure.
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