title: TLR5 or NLRC4 is necessary and sufficient for promotion of humoral immunity by flagellin.
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.
authors.affiliation: Department of Pathology, Emory University, Atlanta, GA 30322, USA.
authors.forename: Matam
authors.initials: M
authors.lastname: Vijay-Kumar
authors.forename: Frederic A
authors.initials: FA
authors.lastname: Carvalho
authors.forename: Jesse D
authors.initials: JD
authors.lastname: Aitken
authors.forename: Nimita H
authors.initials: NH
authors.lastname: Fifadara
authors.forename: Andrew T
authors.initials: AT
authors.lastname: Gewirtz
mesh_terms: D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D002135:Calcium-Binding Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D002460:Cell Line; D054360:Chemokine CXCL1 / Q000378:metabolism; D005408:Flagellin / Q000008:administration & dosage* / Q000494:pharmacology; D054884:Host-Pathogen Interactions; D056724:Immunity, Humoral / Q000235:genetics; D007113:Immunity, Innate; D007114:Immunization; D058847:Inflammasomes; D020382:Interleukin-18 / Q000235:genetics / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D051198:Toll-Like Receptor 5 / Q000235:genetics / Q000276:immunology / Q000378:metabolism*
chemical_list: D051017:Apoptosis Regulatory Proteins; D002135:Calcium-Binding Proteins; D054360:Chemokine CXCL1; D058847:Inflammasomes; D020382:Interleukin-18; C512299:Ipaf protein, mouse; D016328:NF-kappa B; D051198:Toll-Like Receptor 5; D005408:Flagellin