IL‐21 treatment recovers follicular helper T cells and neutralizing antibody production in respiratory syncytial virus infection

Respiratory syncytial virus (RSV) is the major cause of lower respiratory tract infections in children under 1-year-old. RSV vaccines are currently unavailable, and children suffering from multiple reinfections by the same viral strain fail to develop protective responses. Although RSV-specific antibodies can be detected upon infection, these have limited neutralizing capacity. Follicular helper T (Tfh) cells are specialized in providing signals to B cells and help the production and affinity maturation of antibodies, mainly via IL-21 secretion. In this study, we asked if RSV could inhibit Tfh responses. We observed that Tfh cells fail to upregulate IL-21 production upon RSV infection. In the lungs, RSV infection downregulated the expression of IL-21/IL-21R in Tfh cells and upregulated PD-L1 expression in DCs and B cells. PD-L1 blockade during infection recovered IL-21R expression in Tfh cells and increased the secretion of IL-21 in a DC-dependent manner. IL-21 treatment decreased RSV viral load and lung inflammation, inducing the formation of tertiary lymphoid organs (TLOs) in the lung. It also decreased regulatory follicular T cells (Tfr), and increased Tfh cells, B cells, antibody avidity, and neutralization capacity, leading to an overall improved anti-RSV humoral response in infected mice. Passive immunization with purified IgG from IL-21 treated RSV-infected mice protected against RSV infection. Our results unveil a pathway by which RSV affects Tfh cells by increasing PD-L1 expression on antigen-presenting cells (APCs), highlighting the importance of an IL-21/ PD-L1 axis for the generation of protective responses to RSV infection.