Alum adjuvant boosts adaptive immunity by inducing uric acid and activating inflammatory dendritic cells

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Abstract

Alum (aluminum hydroxide) is the most widely used adjuvant in human vaccines, but the mechanism of its adjuvanticity remains unknown. In vitro studies showed no stimulatory effects on dendritic cells (DCs). In the absence of adjuvant, Ag was taken up by lymph node (LN)–resident DCs that acquired soluble Ag via afferent lymphatics, whereas after injection of alum, Ag was taken up, processed, and presented by inflammatory monocytes that migrated from the peritoneum, thus becoming inflammatory DCs that induced a persistent Th2 response. The enhancing effects of alum on both cellular and humoral immunity were completely abolished when CD11c ⁺ monocytes and DCs were conditionally depleted during immunization. Mechanistically, DC-driven responses were abolished in MyD88-deficient mice and after uricase treatment, implying the induction of uric acid. These findings suggest that alum adjuvant is immunogenic by exploiting “nature's adjuvant,” the inflammatory DC through induction of the endogenous danger signal uric acid.

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Most cited references 59

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In vivo depletion of CD11c+ dendritic cells abrogates priming of CD8+ T cells by exogenous cell-associated antigens.

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Cytotoxic T lymphocytes (CTL) respond to antigenic peptides presented on MHC class I molecules. On most cells, these peptides are exclusively of endogenous, cytosolic origin. Bone marrow-derived antigen-presenting cells, however, harbor a unique pathway for MHC I presentation of exogenous antigens. This mechanism permits cross-presentation of pathogen-infected cells and the priming of CTL responses against intracellular microbial infections. Here, we report a novel diphtheria toxin-based system that allows the inducible, short-term ablation of dendritic cells (DC) in vivo. We show that in vivo DC are required to cross-prime CTL precursors. Our results thus define a unique in vivo role of DC, i.e., the sensitization of the immune system for cell-associated antigens. DC-depleted mice fail to mount CTL responses to infection with the intracellular bacterium Listeria monocytogenes and the rodent malaria parasite Plasmodium yoelii.

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TNF/iNOS-producing dendritic cells mediate innate immune defense against bacterial infection.

Natalya Serbina, Thais P. Salazar-Mather, Christine Biron … (2003)

Dendritic cells (DCs) present microbial antigens to T cells and provide inflammatory signals that modulate T cell differentiation. While the role of DCs in adaptive immunity is well established, their involvement in innate immune defenses is less well defined. We have identified a TNF/iNOS-producing (Tip)-DC subset in spleens of Listeria monocytogenes-infected mice that is absent from CCR2-deficient mice. The absence of Tip-DCs results in profound TNF and iNOS deficiencies and an inability to clear primary bacterial infection. CD8 and CD4 T cell responses to L. monocytogenes antigens are preserved in CCR2-deficient mice, indicating that Tip-DCs are not essential for T cell priming. Tip-DCs, as the predominant source of TNF and iNOS during L. monocytogenes infection, orchestrate and mediate innate immune defense against this intracellular bacterial pathogen.

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Author and article information

Journal

Journal ID (nlm-ta): J Exp Med

Journal ID (publisher-id): jem

Title: The Journal of Experimental Medicine

Publisher: The Rockefeller University Press

ISSN (Print): 0022-1007

ISSN (Electronic): 1540-9538

Publication date (Print): 14 April 2008

Volume: 205

Issue: 4

Pages: 869-882

Affiliations

[1 ]Department of Pulmonary Medicine, Erasmus University Medical Centre, 3015 GD Rotterdam, Netherlands

[2 ]Laboratory of Immunoregulation, University Hospital Ghent, 9000 Ghent, Belgium

[3 ]Weizmann Institute, Rehovot 76100, Israel

Author notes

CORRESPONDENCE Bart N. Lambrecht: bart.lambrecht@ 123456ugent.be

Article

Publisher ID: 20071087

DOI: 10.1084/jem.20071087

PMC ID: 2292225

PubMed ID: 18362170

SO-VID: 59a97f2e-97b5-4201-9ac7-c94b8e238d40

History

Date received : 30 May 2007

Date accepted : 28 February 2008

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