Stimulation of local immunity by vaccination is desirable for controlling virus replication in the respiratory tract. However, the local immune stimulatory effects of adjuvanted vaccines administered via non-mucosal route are poorly understood. Here, we clarify the mechanisms by which non-mucosal inoculation of adjuvants stimulates the plasmacytoid dendritic cell (pDC)-dependent IgA response in the lungs. Following systemic inoculation with type 1 interferon (IFN)-inducing adjuvants, type 1 IFN promotes CXCL9/10/11 release from alveolar endothelial and epithelial cells, and recruits CXCR3-expressing pDCs into the lungs. Since adjuvant-activated pulmonary pDCs highly express MHC II, CD80, and CD86, transplantation of such cells into the lungs successfully enhances antigen-specific IgA production by the intranasally sensitized vaccine. In contrast, pDC accumulation in the lungs and subsequent IgA production are impaired in pDC-depleted mice and Ifnar1 mice. Notably, the combination of systemic inoculation with type 1 IFN-inducing adjuvants and intranasal antigen sensitization protects mice against influenza virus infection due to the pDC-dependent IgA response and type I IFN response. Our results provide insights into novel mucosal vaccine strategies using non-mucosal inoculated adjuvants.
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