The relationship between severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) and host immunity is poorly understood. We performed an extensive analysis of immune responses in 32 patients with severe COVID-19, some of whom succumbed. A control population of healthy subjects was included. Patients with COVID-19 had an altered distribution of peripheral blood lymphocytes, with an increased proportion of mature natural killer (NK) cells and low T-cell numbers. NK cells and CD8⁺ T cells overexpressed T-cell immunoglobulin and mucin domain-3 (TIM-3) and CD69. NK cell exhaustion was attested by increased frequencies of programmed cell death protein 1 (PD-1) positive cells and reduced frequencies of natural killer group 2 member D (NKG2D)-, DNAX accessory molecule-1 (DNAM-1)- and sialic acid-binding Ig-like lectin 7 (Siglec-7)-expressing NK cells, associated with a reduced ability to secrete interferon (IFN)γ. Patients with poor outcome showed a contraction of immature CD56^bright and an expansion of mature CD57⁺ FcεRIγ^neg adaptive NK cells compared to survivors. Increased serum levels of IL-6 were also more frequently identified in deceased patients compared to survivors. Of note, monocytes secreted abundant quantities of IL-6, IL-8, and IL-1β which persisted at lower levels several weeks after recovery with concomitant normalization of CD69, PD-1 and TIM-3 expression and restoration of CD8⁺ T cell numbers. A hyperactivated/exhausted immune response dominate in severe SARS-CoV-2 infection, probably driven by an uncontrolled secretion of inflammatory cytokines by monocytes. These findings unveil a unique immunological profile in COVID-19 patients that will help to design effective stage-specific treatments for this potentially deadly disease.

严重急性呼吸系统综合症冠状病毒2（SARS-CoV-2）与宿主免疫之间的关系知之甚少。我们对 32 名重症 COVID-19 患者的免疫反应进行了广泛分析，其中一些患者已经死亡。包括健康受试者的对照人群。COVID-19 患者的外周血淋巴细胞分布发生改变，成熟自然杀伤 (NK) 细胞比例增加，T 细胞数量减少。NK 细胞和 CD8 ⁺T 细胞过表达 T 细胞免疫球蛋白和粘蛋白结构域 3 (TIM-3) 和 CD69。NK 细胞衰竭通过程序性细胞死亡蛋白 1 (PD-1) 阳性细胞的频率增加和自然杀伤组 2 成员 D (NKG2D)-、DNAX 辅助分子-1 (DNAM-1)- 和唾液酸的频率降低来证明结合 Ig 样凝集素 7 (Siglec-7) 的 NK 细胞，与分泌干扰素 (IFN)γ 的能力降低有关。结果不佳的患者显示未成熟 CD56^明亮收缩和成熟 CD57 ⁺ FcεRIγ^阴性扩增与幸存者相比，适应性 NK 细胞。与幸存者相比，死亡患者的血清 IL-6 水平升高的频率也更高。值得注意的是，单核细胞分泌大量的 IL-6、IL-8 和 IL-1β，在恢复数周后持续保持较低水平，同时 CD69、PD-1 和 TIM-3 表达正常化以及 CD8 ⁺ T 细胞恢复数字。在严重的 SARS-CoV-2 感染中，过度激活/耗尽的免疫反应占主导地位，这可能是由单核细胞不受控制地分泌炎性细胞因子驱动的。这些发现揭示了 COVID-19 患者的独特免疫学特征，这将有助于为这种潜在的致命疾病设计有效的阶段特异性治疗方法。