ABSTRACT
Effective humoral immune responses require well-orchestrated cellular interactions between B and T follicular helper (Tfh) cells. Whether this interaction is impaired and associated with COVID-19 disease severity is unknown. Here, longitudinal acute and convalescent blood samples from 49 COVID-19 patients across mild to severe disease were analysed. We found that during acute infection activated and SARS-CoV-2-specific circulating Tfh (cTfh) cell frequencies expanded with increasing disease severity. The frequency of activated and SARS-CoV-2-specific cTfh cells correlated with plasmablast frequencies and SARS-CoV-2 antibody titers, avidity and neutralization. Furthermore, cTfh cells but not other memory CD4 T cells, isolated from severe patients induced more pronounced differentiation of autologous plasmablast and antibody production in vitro compared to cTfh cells isolated from mild patients. However, the development of virus-specific cTfh cells was delayed in patients that displayed or later developed severe disease compared to those that maintained a mild or moderate disease. This correlated with a delayed induction of high-avidity and neutralizing virus-specific antibodies. Our study therefore suggests that impaired generation of functional virus-specific cTfh cells delays the production of high-quality antibodies to combat the infection at an early stage and thereby enabling progression to more severe COVID-19 disease.