Individuals with potential exposure to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) do not necessarily develop PCR or antibody positivity, suggesting that some individuals may clear subclinical infection before seroconversion. T cells can contribute to the rapid clearance of SARS-CoV-2 and other coronavirus infections^1,2,3. Here we hypothesize that pre-existing memory T cell responses, with cross-protective potential against SARS-CoV-2 (refs. ^{4,5,6,7,8,9,10,11}), would expand in vivo to support rapid viral control, aborting infection. We measured SARS-CoV-2-reactive T cells, including those against the early transcribed replication–transcription complex (RTC)^12,13, in intensively monitored healthcare workers (HCWs) who tested repeatedly negative according to PCR, antibody binding and neutralization assays (seronegative HCWs (SN-HCWs)). SN-HCWs had stronger, more multispecific memory T cells compared with a cohort of unexposed individuals from before the pandemic (prepandemic cohort), and these cells were more frequently directed against the RTC than the structural-protein-dominated responses observed after detectable infection (matched concurrent cohort). SN-HCWs with the strongest RTC-specific T cells had an increase in IFI27, a robust early innate signature of SARS-CoV-2 (ref. ¹⁴), suggesting abortive infection. RNA polymerase within RTC was the largest region of high sequence conservation across human seasonal coronaviruses (HCoV) and SARS-CoV-2 clades. RNA polymerase was preferentially targeted (among the regions tested) by T cells from prepandemic cohorts and SN-HCWs. RTC-epitope-specific T cells that cross-recognized HCoV variants were identified in SN-HCWs. Enriched pre-existing RNA-polymerase-specific T cells expanded in vivo to preferentially accumulate in the memory response after putative abortive compared to overt SARS-CoV-2 infection. Our data highlight RTC-specific T cells as targets for vaccines against endemic and emerging Coronaviridae.

可能接触过严重急性呼吸综合征冠状病毒 2 (SARS-CoV-2) 的个体不一定会出现 PCR 或抗体阳性，这表明某些个体可能会在血清转化前清除亚临床感染。T 细胞有助于快速清除 SARS-CoV-2 和其他冠状病毒感染^1,2,3。在这里，我们假设预先存在的记忆 T 细胞反应具有针对 SARS-CoV-2 的交叉保护潜力（参考文献^{4,5,6,7,8,9,10,11}），将在体内扩展以支持快速控制病毒，终止感染。我们在严密监控的医护人员 (HCW) 中测量了 SARS-CoV-2 反应性 T 细胞，包括针对早期转录复制-转录复合物 (RTC) 的 T 细胞 12,13，这些医护人员根据^PCR 、抗体结合和中和测定法多次检测结果呈阴性（血清阴性医护人员 (SN-HCW)）。与大流行前未暴露的人群（大流行前队列）相比，SN-HCW 具有更强、更多特异性的记忆 T 细胞，并且这些细胞更频繁地针对 RTC，而不是在可检测到的感染后观察到的以结构蛋白为主的反应。匹配的并发队列）。具有最强 RTC 特异性 T 细胞的 SN-HCW 的IFI27有所增加，IFI27 是 SARS-CoV-2 强有力的早期先天特征（参考文献¹⁴），表明感染流产。RTC 内的 RNA 聚合酶是人类季节性冠状病毒 (HCoV) 和 SARS-CoV-2 进化枝中最大的高序列保守区域。RNA 聚合酶优先被来自大流行前人群和 SN-HCW 的 T 细胞靶向（在测试的区域中）。在 SN-HCW 中鉴定出交叉识别 HCoV 变体的 RTC 表位特异性 T 细胞。与明显的 SARS-CoV-2 感染相比，富集的预先存在的 RNA 聚合酶特异性 T 细胞在体内扩增，在假定流产后优先在记忆反应中积累。我们的数据强调 RTC 特异性 T 细胞可作为针对地方性和新兴冠状病毒科疫苗的靶标。