title: Maximal adjuvant activity of nasally delivered IL-1α requires adjuvant-responsive CD11c(+) cells and does not correlate with adjuvant-induced in vivo cytokine production.
abstract: IL-1 has been shown to have strong mucosal adjuvant activities, but little is known about its mechanism of action. We vaccinated IL-1R1 bone marrow (BM) chimeric mice to determine whether IL-1R1 expression on stromal cells or hematopoietic cells was sufficient for the maximal adjuvant activity of nasally delivered IL-1α as determined by the acute induction of cytokine responses and induction of Bacillus anthracis lethal factor (LF)-specific adaptive immunity. Cytokine and chemokine responses induced by vaccination with IL-1α were predominantly derived from the stromal cell compartment and included G-CSF, IL-6, IL-13, MCP-1, and keratinocyte chemoattractant. Nasal vaccination of Il1r1(-/-) (knock-out [KO]) mice given wild-type (WT) BM (WT→KO) and WT→WT mice with LF + IL-1α induced maximal adaptive immune responses, whereas vaccination of WT mice given Il1r1(-/-) BM (KO→WT) resulted in significantly decreased production of LF-specific serum IgG, IgG subclasses, lethal toxin-neutralizing Abs, and mucosal IgA compared with WT→KO and WT→WT mice (p < 0.05). IL-1α adjuvant activity was not dependent on mast cells. However, the ability of IL-1α to induce serum LF-specific IgG2c and lethal toxin-neutralizing Abs was significantly impaired in CD11c-Myd88(-/-) mice when compared with WT mice (p < 0.05). Our results suggest that CD11c(+) cells must be directly activated by nasally administered IL-1α for maximal adjuvant activity and that, although stromal cells are required for maximal adjuvant-induced cytokine production, the adjuvant-induced stromal cell cytokine responses are not required for effective induction of adaptive immunity.
authors.affiliation: Department of Pathology, Duke University Medical Center, Durham, NC 27710, USA.
authors.forename: Afton L
authors.initials: AL
authors.lastname: Thompson
authors.forename: Brandi T
authors.initials: BT
authors.lastname: Johnson
authors.forename: Gregory D
authors.initials: GD
authors.lastname: Sempowski
authors.forename: Michael D
authors.initials: MD
authors.lastname: Gunn
authors.forename: Baidong
authors.initials: B
authors.lastname: Hou
authors.forename: Anthony L
authors.initials: AL
authors.lastname: DeFranco
authors.forename: Herman F
authors.initials: HF
authors.lastname: Staats
mesh_terms: D000276:Adjuvants, Immunologic / Q000008:administration & dosage*; D000818:Animals; D000942:Antigens, Bacterial / Q000008:administration & dosage / Q000276:immunology; D001427:Bacterial Toxins / Q000008:administration & dosage / Q000276:immunology; D039521:CD11c Antigen / Q000276:immunology / Q000378:metabolism; D002469:Cell Separation; D016207:Cytokines / Q000096:biosynthesis* / Q000276:immunology; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005434:Flow Cytometry; D018928:Immunity, Mucosal / Q000276:immunology*; D053582:Interleukin-1alpha / Q000008:administration & dosage* / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009000:Monocytes / Q000276:immunology / Q000378:metabolism; D011828:Radiation Chimera; D014611:Vaccination / Q000379:methods*
chemical_list: D000276:Adjuvants, Immunologic; D000942:Antigens, Bacterial; D001427:Bacterial Toxins; D039521:CD11c Antigen; D016207:Cytokines; D053582:Interleukin-1alpha; C030325:anthrax toxin