Table_1_Age-dependent NK cell dysfunctions in severe COVID-19 patients.docx

Natural Killer (NK) cells are key innate effectors of antiviral immune response, and their activity changes in ageing and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Here, we investigated the age-related changes of NK cell phenotype and function during SARS-CoV-2 infection, by comparing adult and elderly patients both requiring mechanical ventilation. Adult patients had a reduced number of total NK cells, while elderly showed a peculiar skewing of NK cell subsets towards the CD56lowCD16high and CD56neg phenotypes, expressing activation markers and check-point inhibitory receptors. Although NK cell degranulation ability is significantly compromised in both cohorts, IFN-γ production is impaired only in adult patients in a TGF-β−dependent manner. This inhibitory effect was associated with a shorter hospitalization time of adult patients suggesting a role for TGF-β in preventing an excessive NK cell activation and systemic inflammation. Our data highlight an age-dependent role of NK cells in shaping SARS-CoV-2 infection toward a pathophysiological evolution.自然杀伤（Natural Killer, NK）细胞是抗病毒免疫应答的关键固有免疫效应细胞，其活性会随衰老及严重急性呼吸综合征冠状病毒2（SARS-CoV-2）感染发生动态变化。本研究通过对比均需机械通气的成年与老年患者，探究了SARS-CoV-2感染期间NK细胞表型与功能的年龄相关变化。研究结果显示，成年患者的总NK细胞数量减少；而老年患者的NK细胞亚群则出现特异性偏移，偏向CD56lowCD16high与CD56neg表型，此类亚群可表达活化标志物与免疫检查点抑制性受体。尽管两组患者的NK细胞脱颗粒能力均显著受损，但仅成年患者的γ干扰素（IFN-γ）产生能力以转化生长因子-β（TGF-β）依赖的方式受到抑制。该抑制效应与成年患者更短的住院时长存在关联，提示TGF-β可通过抑制NK细胞过度活化与全身炎症反应发挥调控作用。本研究数据揭示了NK细胞在驱动SARS-CoV-2感染向病理生理进程演变过程中的年龄依赖性作用。