Single-cell transcriptomic analysis of SARS-CoV-2 reactive CD4⁺T cells

The contribution of CD4⁺T cells to protective or pathogenic immune responses to SARS-CoV-2 infection remains unknown. Here, we present large-scale single-cell transcriptomic analysis of viral antigen-reactive CD4⁺T cells from 32 COVID-19 patients. In patients with severe disease compared to mild disease, we found increased proportions of cytotoxic follicular helper (T_FH) cells and cytotoxic T helper cells (CD4-CTLs) responding to SARS-CoV-2, and reduced proportion of SARS-CoV-2 reactive regulatory T cells. Importantly, the CD4-CTLs were highly enriched for the expression of transcripts encoding chemokines that are involved in the recruitment of myeloid cells and dendritic cells to the sites of viral infection. Polyfunctional T helper (T_H)1 cells 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 so far unprecedented insights into the gene expression patterns of SARS-CoV-2 reactive CD4⁺T cells in distinct disease severities.