Low avidity T cell responses to SARS-CoV-2 in unexposed individuals and severe COVID-19. 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. Overall design: Single-cell sequencing of 6 unexposed and 14 COVID-19 patients

针对严重急性呼吸综合征冠状病毒2型（SARS-CoV-2）的预存记忆T细胞，在部分未暴露人群中已被检出，且有研究提示此类T细胞可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细胞仅具备较低的功能亲和力。此类T细胞具有多种高度可变的交叉反应特性，且此类反应并不局限于普通感冒冠状病毒。新型冠状病毒肺炎（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，即便所有受试者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。在重型而非轻型新型冠状病毒肺炎患者体内，尽管针对SARS-CoV-2的T细胞频率显著升高，但其仍表现出较低的功能亲和力以及克隆扩增能力受损的特征。本研究数据对普通感冒冠状病毒在新型冠状病毒肺炎防护中的核心保护作用提出了质疑。相反，我们提出，预存的低亲和力T细胞记忆可能促成了过度但亲和力低下的T细胞应答——此类应答正是本研究中鉴定出的重型新型冠状病毒肺炎的标志性特征。实验整体设计：对6名未暴露个体与14名新型冠状病毒肺炎患者开展单细胞测序。