Interleukin (IL)-33 is a multifunctional cytokine that mediates type 2 dominated immune responses. In contrast, the role of IL-33 during viral vaccination, which often aims to induce type 1 immunity, has not been fully investigated. Here we examined the effects of IL-33 on influenza vaccine responses. We found that intranasal co-administration of IL-33 with an inactivated influenza virus vaccine increases the vaccine efficacy against influenza infection, not only with the homologous strain, but also heterologous strains including the 2009 H1N1 influenza pandemic strain. The cross-protection was dependent on group 2 innate lymphoid cells (ILC2s), as the beneficial effect of IL-33 on vaccine efficacy was abrogated in ILC2-deficient C57BL/6
Il7r
P
Cre/+
P
Rora
P
fl/fl
P mice. Further, mechanistic studies revealed that IL-33 activated ILC2s potentiate vaccine efficacy by enhancing mucosal humoral immunity, particularly IgA responses, potentially via a Th2 cytokine dependent manner. Our results demonstrate that IL-33-mediated activation of ILC2s is a critical early event that is important for the induction of mucosal humoral immunity, which in turn is responsible for cross-strain protection against influenza. Thus, we reveal a previously unrecognized role for the IL-33/ILC2 axis in establishing broadly protective and long-lasting humoral mucosal immunity against influenza – knowledge that may help develop a universal influenza vaccine.
Importance
Current influenza vaccines, although capable of protecting against predicted viruses/strains included in the vaccine, are inept at providing cross-protection against emerging/novel strains. Thus, we are in critical need for a universal vaccine that can protect against a wide range of influenza viruses. Our novel findings show that a mucosal vaccination strategy involving the activation of lung ILC2s is highly effective in eliciting cross-protective humoral immunity in the lungs. This suggests that the biology of lung ILC2s can be exploited to increase the cross-reactivity of commercially available influenza subunit vaccines.
Consecutive CT in vivo lung imaging as quantitative parameter of influenza vaccine efficacy in the ferret model
