TLR5 or NLRC4 is necessary and sufficient for promotion of humoral immunity by flagellin

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Abstract
The fact that some TLR‐based vaccine adjuvants maintain function in TLR‐deficient hosts highlights that their mechanism of function remains incompletely understood. Thus, we examined the ability of flagellin to induce cytokines and elicit/promote murine antibody responses upon deletion of the flagellin receptors TLR5 and/or NLRC4 (also referred to as IPAF) using a prime/boost regimen. In TLR5‐KO mice, flagellin failed to induce NF‐κB‐regulated cytokines such as keratinocyte‐derived chemokine (CXCL1) but induced WT levels of the inflammasome cytokine IL‐18 (IL‐1F4). Conversely, in NLRC4‐KO mice, flagellin induced keratinocyte‐derived chemokine, but not IL‐18, whereas TLR5/NLRC4‐DKO lacked induction of all cytokines measured. Flagellin/ovalbumin treatment resulted in high‐antibody titers to both flagellin and ovalbumin in WT, TLR5‐KO and DKO mice but did not elicit antibodies to either in TLR5/NLRC4‐DKO mice. Thus, flagellin's ability to elicit/promote humoral immunity requires a germ‐line‐encoded receptor capable of recognizing this molecule. Such promotion of adaptive immunity can be effectively driven by either TLR5‐mediated activation of NF‐κB or NLRC4‐mediated activation of the inflammasome.