Imbalance of regulatory and cytotoxic SARS-CoV-2-reactive CD4+ T cells in COVID-19

Meckiff, Benjamin J.; Ramírez-Suástegui, Ciro; Fajardo, Vicente; Chee, Serena J.; Kusnadi, Anthony; Simon, Hayley; Eschweiler, Simon; 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 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 (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 (TREG). Importantly, in hospitalized COVID-19 patients, a strong cytotoxic TFH response was observed early in the illness which correlated negatively with antibody levels to SARS-CoV-2 spike protein. Polyfunctional T helper (TH)1 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 insights into the gene expression patterns of SARS-CoV-2-reactive CD4+ T cells in distinct disease severities.