Low avidity T cell responses to SARS-CoV-2 in unexposed individuals and severe COVID-19

Pre-existing memory T-cells against SARS-CoV-2 are present in a fraction of unexposed individuals and their induction by common cold corona viruses (CCCoVs) infection is suggested. Here we demonstrate that SARS-CoV-2-reactive T-cells were present in the memory compartment of virtually all unexposed individuals but possessed only low functional avidity. They harbored multiple, highly variable cross-reactivities that were not restricted to CCCoVs. Cross-reactivity to CCCoV was almost absent in COVID-19 patients. This was irrespective of strong T-cell memory against CCCoV in all donors. In severe but not mild COVID-19, SARS-CoV-2-specific T-cells also displayed low functional avidity and reduced clonal expansion, despite strongly increased frequencies. Our data question a major protective role of CCCoV for COVID-19. Instead, we suggest that a low avidity pre-existing T-cell memory may contribute to the excessive but low avidity T-cell responses, which we identified here as a hallmark of severe COVID-19. Single-cell sequencing of 6 unexposed and 14 COVID-19 patients

已有研究提示，部分未暴露于严重急性呼吸综合征冠状病毒2（SARS-CoV-2）的个体体内已存在针对该病毒的预存记忆T细胞，且此类T细胞可能由普通感冒冠状病毒（common cold corona viruses, CCCoVs）感染诱导产生。本研究证实，几乎所有未暴露个体的记忆细胞库中均存在可识别SARS-CoV-2的T细胞，但此类T细胞仅表现出较低的功能亲和力。这些T细胞具备多种高度可变的交叉反应性，且其识别范围并不局限于普通感冒冠状病毒。COVID-19患者体内几乎不存在针对普通感冒冠状病毒的交叉反应性T细胞，即便所有受试个体体内均存在针对普通感冒冠状病毒的强效T细胞记忆，这一现象仍不受影响。在重症而非轻症COVID-19患者体内，尽管针对SARS-CoV-2的T细胞频率显著升高，但此类特异性T细胞同样表现出较低的功能亲和力以及克隆扩增能力受损的情况。本研究数据对“普通感冒冠状病毒对COVID-19具有主要保护作用”这一观点提出了质疑。与之相反，我们提出：预存的低亲和力T细胞记忆，可能是引发过度但低亲和力T细胞应答的原因之一——此类应答正是本研究确认的重症COVID-19的标志性特征。本研究针对6名未暴露个体与14名COVID-19患者开展了单细胞测序实验。