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

Meckiff, Benjamin J.; Ramírez-Suástegui, Ciro; Fajardo, Vicente; Chee, Serena J; Kusnadi, Anthony; Simon, Hayley; Grifoni, Alba; Pelosi, Emanuela; Weiskopf, Daniela; Sette, Alessandro; Ay, Ferhat; Seumois, Grégory; Ottensmeier, Christian H; Vijayanand, Pandurangan

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 (TFH) 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 (TH)1 cells and TH17 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.