Data_Sheet_1_Low avidity circulating SARS-CoV-2 reactive CD8+ T cells with proinflammatory TEMRA phenotype are associated with post-acute sequelae of COVID-19.PDF

The role of adaptive SARS-CoV-2 specific immunity in post-acute sequelae of COVID-19 (PASC) is not well explored, although a growing population of convalescent COVID-19 patients with manifestation of PASC is observed. We analyzed the SARS-CoV-2-specific immune response, via pseudovirus neutralizing assay and multiparametric flow cytometry in 40 post-acute sequelae of COVID-19 patients with non-specific PASC manifestation and 15 COVID-19 convalescent healthy donors. Although frequencies of SARS-CoV-2-reactive CD4+ T cells were similar between the studied cohorts, a stronger SARS-CoV-2 reactive CD8+ T cell response, characterized by IFNγ production and predominant TEMRA phenotype but low functional TCR avidity was detected in PASC patients compared to controls. Of interest, high avidity SARS-CoV-2-reactive CD4+ and CD8+ T cells were comparable between the groups demonstrating sufficient cellular antiviral response in PASC. In line with the cellular immunity, neutralizing capacity in PASC patients was not inferior compared to controls. In conclusion, our data suggest that PASC may be driven by an inflammatory response triggered by an expanded population of low avidity SARS-CoV-2 reactive pro-inflammatory CD8+ T cells. These pro-inflammatory T cells with TEMRA phenotype are known to be activated by a low or even without TCR stimulation and lead to a tissue damage. Further studies including animal models are required for a better understanding of underlying immunopathogensis. Summary: A CD8+ driven persistent inflammatory response triggered by SARS-CoV-2 may be responsible for the observed sequelae in PASC patients.

严重急性呼吸综合征冠状病毒2（SARS-CoV-2）特异性适应性免疫在新冠急性感染后后遗症（Post-acute sequelae of COVID-19, PASC）中的作用尚未得到充分研究，尽管临床中观察到出现PASC表现的新冠康复患者群体正逐渐扩大。
本研究通过假病毒中和试验与多参数流式细胞术，对40例出现非特异性PASC表现的患者及15例新冠康复健康供者的SARS-CoV-2特异性免疫应答进行了分析。
尽管两组研究队列中SARS-CoV-2反应性CD4+ T细胞的频率相似，但与对照组相比，PASC患者体内检测到更强的SARS-CoV-2反应性CD8+ T细胞应答，其特征为干扰素γ（IFNγ）产生、表型以终末分化记忆性T细胞（TEMRA）为主，但功能T细胞受体（TCR）亲和力较低。
值得注意的是，两组中高亲和力SARS-CoV-2反应性CD4+与CD8+ T细胞水平相当，表明PASC患者体内存在充分的细胞抗病毒应答。
与细胞免疫结果一致，PASC患者的中和能力并不劣于对照组。
综上，本研究数据表明，PASC可能由扩增的低亲和力SARS-CoV-2反应性促炎CD8+ T细胞群体触发的炎症反应所驱动。
这类具有TEMRA表型的促炎T细胞可通过低水平甚至无TCR刺激的方式被激活，并引发组织损伤。
未来需开展包括动物模型在内的进一步研究，以更好地阐明其潜在的免疫病理机制。
研究总结：由SARS-CoV-2触发的、以CD8+ T细胞介导的持续性炎症反应，可能是PASC患者出现上述后遗症的原因。