Memory B cells targeting SARS-CoV-2 spike protein and their dependence on CD4+ T cell help

Memory B cells seem to be more durable than antibodies and thus crucial for the long-term immunity against SARS-CoV-2 infection. Here we investigate SARS-CoV-2 spike-specific memory B cells and their dependence on CD4+ T cell help in different settings of COVID-19. Compared to severely ill, individuals who recovered from mild COVID-19 develop fewer but functionally superior spike-specific memory B cells. Generation and affinity maturation of these cells is best associated with IL-21+CD4+ T cells in recovered individuals and CD40L+CD4+ T cells in severely ill individuals. The increased activation and exhaustion of memory B cells observed during COVID-19 correlates with CD4+ T cell functions. Intriguingly, CD4+ T cells recognizing membrane protein show a stronger association with spike-specific memory B cells than those recognizing spike or nucleocapsid proteins. Overall, we have identified CD4+ T cell subsets associated with the generation of B cell memory during SARS-CoV-2 infection.