The contribution of CD4⁺ T cells to protective or pathogenic immune responses to SARS-CoV-2 infection remains unknown. Here, we present single-cell transcriptomic analysis of >100,000 viral antigen-reactive CD4⁺ T cells from 40 COVID-19 patients. In hospitalized patients compared to non-hospitalized patients, we found increased proportions of cytotoxic follicular helper cells and cytotoxic T helper (T_H) cells (CD4-CTLs) responding to SARS-CoV-2 and reduced proportion of SARS-CoV-2-reactive regulatory T cells (T_REG). Importantly, in hospitalized COVID-19 patients, a strong cytotoxic T_FH response was observed early in the illness, which correlated negatively with antibody levels to SARS-CoV-2 spike protein. Polyfunctional T_H1 and T_H17 cell subsets were underrepresented in the repertoire of SARS-CoV-2-reactive CD4⁺ T cells compared to influenza-reactive CD4⁺ T cells. Together, our analyses provide insights into the gene expression patterns of SARS-CoV-2-reactive CD4⁺ T cells in distinct disease severities.

CD4 ⁺ T 细胞对 SARS-CoV-2 感染的保护性或致病性免疫反应的贡献仍不清楚。在这里，我们对来自 40 名 COVID-19 患者的超过 100,000 个病毒抗原反应性 CD4 ⁺ T 细胞进行了单细胞转录组分析。与非住院患者相比，在住院患者中，我们发现对 SARS-CoV-2 做出反应的细胞毒性滤泡辅助细胞和细胞毒性 T 辅助细胞 (T _H ) (CD4-CTL) 的比例增加，而 SARS-CoV-2- 的比例减少反应性调节性 T 细胞 (T _REG )。重要的是，在住院的 COVID-19 患者中，在疾病早期观察到强烈的细胞毒性 T _FH反应，这与 SARS-CoV-2 刺突蛋白的抗体水平呈负相关。与流感反应性 CD4 ⁺ T 细胞相比，多功能 T _H 1 和 T _H 17 细胞亚群在 SARS-CoV-2 反应性 CD4 ⁺ T 细胞库中代表性不足。总之，我们的分析提供了对 SARS-CoV-2 反应性 CD4 ⁺ T 细胞在不同疾病严重程度下的基因表达模式的见解。