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

  • Vijay-Kumar M
  • Carvalho F
  • Aitken J
 et al. 
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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-kappaB-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-kappaB or NLRC4-mediated activation of the inflammasome.

Author-supplied keywords

  • Antibodies
  • IL-18
  • Innate immunity
  • NF-kB
  • NLRC4

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  • Matam Vijay-Kumar

  • Frederic A. Carvalho

  • Jesse D. Aitken

  • Nimita H. Fifadara

  • Andrew T. Gewirtz

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