CD4⁺ T cells reactive against SARS-CoV-2 can be found in unexposed individuals, and these are suggested to arise in response to common cold coronavirus (CCCoV) infection. Here, we utilized SARS-CoV-2-reactive CD4⁺ T cell enrichment to examine the antigen avidity and clonality of these cells, as well as the relative contribution of CCCoV cross-reactivity. SARS-CoV-2-reactive CD4⁺ memory T cells were present in virtually all unexposed individuals examined, displaying low functional avidity and multiple, highly variable cross-reactivities that were not restricted to CCCoVs. SARS-CoV-2-reactive CD4⁺ T cells from COVID-19 patients lacked cross-reactivity to CCCoVs, irrespective of strong memory T cell responses against CCCoV in all donors analyzed. In severe but not mild COVID-19, SARS-CoV-2-specific T cells displayed low functional avidity and clonality, despite increased frequencies. Our findings identify low-avidity CD4⁺ T cell responses as a hallmark of severe COVID-19 and argue against a protective role for CCCoV-reactive T cells in SARS-CoV-2 infection.

CD4 ⁺ T 细胞对 SARS-CoV-2 具有反应性，可在未接触过的个体中发现，这些细胞被认为是针对普通感冒冠状病毒 (CCCoV) 感染而产生的。在这里，我们利用 SARS-CoV-2 反应性 CD4 ⁺ T 细胞富集来检查这些细胞的抗原亲和力和克隆性，以及 CCCoV 交叉反应性的相对贡献。几乎所有未接触过的受检个体中都存在 SARS-CoV-2 反应性 CD4 ⁺记忆 T 细胞，表现出低功能亲和力和多种、高度可变的交叉反应性，且不限于 CCCoV。尽管在所有分析的供体中针对 CCCoV 的记忆 T 细胞有强烈的反应，但来自 COVID-19 患者的 SARS-CoV-2 反应性 CD4 ⁺ T 细胞缺乏与 CCCoV 的交叉反应性。在严重而非轻度的 COVID-19 中，SARS-CoV-2 特异性 T 细胞表现出较低的功能亲和力和克隆性，尽管频率有所增加。我们的研究结果将低亲和力 CD4 ⁺ T 细胞反应确定为严重 COVID-19 的标志，并反对 CCCoV 反应性 T 细胞在 SARS-CoV-2 感染中的保护作用。