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Maximal adjuvant activity of nasally delivered IL-1 requires adjuvant-responsive CD11c(+) cells and does not correlate with adjuvant-induced in vivo cytokine production

Thompson, AL;Johnson, BT;Sempowski, GD;Gunn, MD;Hou, B;DeFranco, AL;Staats, HF;

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-1 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-1 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 (WTKO) and WTWT mice with LF + IL-1 induced maximal adaptive immune responses, whereas vaccination of WT mice given Il1r1(-/-) BM (KOWT) resulted in significantly decreased production of LF-specific serum IgG, IgG subclasses, lethal toxin-neutralizing Abs, and mucosal IgA compared with WTKO and WTWT mice (p < 0.05). IL-1 adjuvant activity was not dependent on mast cells. However, the ability of IL-1 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-1 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.