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.
Effective humoral immune responses require well-orchestrated B and T follicular helper (Tfh) cell interactions. Whether these interactions are impaired and associated with COVID-19 disease severity is unclear. Here, longitudinal blood samples across COVID-19 disease severity are analysed. We find that during acute infection SARS-CoV-2-specific circulating Tfh (cTfh) cells expand with disease severity. SARS-CoV-2-specific cTfh cell frequencies correlate with plasmablast frequencies and SARS-CoV-2 antibody titers, avidity and neutralization. Furthermore, cTfh cells but not other memory CD4 T cells, from severe patients better induce plasmablast differentiation and antibody production compared to cTfh cells from mild patients. However, virus-specific cTfh cell development is delayed in patients that display or later develop severe disease compared to those with mild disease, which correlates with delayed induction of high-avidity neutralizing antibodies. Our study suggests that impaired generation of functional virus-specific cTfh cells delays high-quality antibody production at an early stage, potentially enabling progression to severe disease.
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