Induction of adaptive immunity by flagellin does not require TLR5 or robust innate immune activation

The effectiveness of vaccine adjuvants is attributed to their activation of robust and varied innate immune events, which in turn may promote protective adaptive immunity. Flagellin (flg), a TLR5‐ and MyD88‐dependent immunogen, is a potent inducer of both arms of immunity, and thus may be a good vaccine adjuvant candidate. We hypothesized that TLR5 is critical for flagellin to induce both innate and adaptive immunity to co‐administered OVA. Surprisingly, TLR5KO mice boosted with flg+OVA developed strong OVA‐specific IgG titers, suggesting that TLR5 is not needed for flagellin.s adjuvanticity. Responses were not due to common contaminants, as flg‐treated TLR5TLR4DKO and TLR5TLR2DKO mice both made comparable Ab titers to TLR5KO. Adjuvants are thought to function via activation of early immune events. Flg‐treated TLR5KO mice lacked systemic IL‐12, TNFα, IL‐17, and RANTES measured over 24hr, and made very low levels of KC, IL‐6, IL‐1α, MCP‐1, and G‐CSF. No upregulation of CD80, 86, or 40 were detected on splenic DCs removed 6hr after I.P. flg injection of TLR5KO mice. These data indicate flagellin.s adjuvanticity does not require TLR5, detectable DC activation, or the relatively high serum cytokine levels found in WT mice. Our results suggest that vaccine adjuvants may not necessarily require robust innate immune events to generate effective adaptive immune responses.