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. 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 interleukin (IL) 21 secretion. In this study, we evaluated whether 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/interleukin‐21 receptor (IL‐21R) in Tfh cells and upregulated programmed death‐ligand 1 (PD‐L1) expression in dendritic cells (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 in the lung. It also decreased regulatory follicular T cells, 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 immunoglobulin G 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, highlighting the importance of an IL‐21–PD‐L1 axis for the generation of protective responses to RSV infection. Respiratory syncytial virus (RSV) infection impairs interleukin (IL)‐21 secretion by follicular helper T cells (Tfh) via programmed death‐ligand 1 (PD‐L1) induction in lung dendritic cells. In this study, we showed that PD‐L1 blockade can upregulate IL‐21 secretion by lung Tfh cells. Low levels of IL‐21 lead to poor RSV‐specific humoral immune responses, low immunoglobulin G and immunoglobulin E titer, avidity and neutralization capacity, and IL‐21 treatment induces formation of tertiary lymphoid organs and restores the humoral response, resulting in less lung inflammation and RSV titers.