SARS-CoV-2-reactive T cells are detected in some healthy unexposed individuals. Human studies indicate these T cells could be elicited by the common cold coronavirus OC43. To directly test this assumption and define the role of OC43-elicited T cells that are cross-reactive with SARS-CoV-2, we develop a model of sequential infections with OC43 followed by SARS-CoV-2 in HLA-B*0702 and HLA-DRB1*0101 Ifnar1^−/− transgenic mice. We find that OC43 infection can elicit polyfunctional CD8⁺ and CD4⁺ effector T cells that cross-react with SARS-CoV-2 peptides. Furthermore, pre-exposure to OC43 reduces subsequent SARS-CoV-2 infection and disease in the lung for a short-term in HLA-DRB1*0101 Ifnar1^−/− transgenic mice, and a longer-term in HLA-B*0702 Ifnar1^−/− transgenic mice. Depletion of CD4⁺ T cells in HLA-DRB1*0101 Ifnar1^−/− transgenic mice with prior OC43 exposure results in increased viral burden in the lung but no change in virus-induced lung damage following infection with SARS-CoV-2 (versus CD4⁺ T cell-sufficient mice), demonstrating that the OC43-elicited SARS-CoV-2 cross-reactive T cell-mediated cross-protection against SARS-CoV-2 is partially dependent on CD4⁺ T cells. These findings contribute to our understanding of the origin of pre-existing SARS-CoV-2-reactive T cells and their effects on SARS-CoV-2 clinical outcomes, and also carry implications for development of broadly protective betacoronavirus vaccines.

在一些未暴露的健康个体中检测到 SARS-CoV-2 反应性 T 细胞。人类研究表明，这些 T 细胞可能由普通感冒冠状病毒 OC43 引发。为了直接检验这一假设并定义 OC43 引发的与 SARS-CoV-2 交叉反应的 T 细胞的作用，我们开发了一个模型，在 HLA-B*0702 和 HLA-DRB1*0101 Ifnar1^-/- 转基因小鼠中，先用 OC43 然后是 SARS-CoV-2。我们发现 OC43 感染可以引发与 SARS-CoV-2 肽交叉反应的多功能 CD8 ⁺ 和 CD4 ⁺ 效应 T 细胞。此外，在 HLA-DRB1*0101 Ifnar1 ^{- / -} 转基因小鼠中，预先暴露于 OC43 可在短期内减少随后的 SARS-CoV-2 感染和肺部疾病，在 HLA-B * 0702 Ifnar1 ^{- /-} 转基因小鼠中可长期减少。在先前暴露于 OC43 的 HLA-DRB1*0101 Ifnar1^-/− 转基因小鼠中 CD4⁺ T 细胞的耗竭导致肺部病毒载量增加，但感染 SARS-CoV-2 后病毒诱导的肺损伤没有变化（与 CD4⁺ T 细胞充足的小鼠相比），表明 OC43 引发的 SARS-CoV-2 交叉反应性 T 细胞介导的针对 SARS-CoV-2 的交叉保护部分依赖于 CD4⁺T 细胞。这些发现有助于我们了解预先存在的 SARS-CoV-2 反应性 T 细胞的来源及其对 SARS-CoV-2 临床结果的影响，也对开发具有广泛保护作用的 β 冠状病毒疫苗具有意义。