title: DNA released from dying host cells mediates aluminum adjuvant activity.
abstract: Aluminum-based adjuvants (aluminum salts or alum) are widely used in human vaccination, although their mechanisms of action are poorly understood. Here we report that, in mice, alum causes cell death and the subsequent release of host cell DNA, which acts as a potent endogenous immunostimulatory signal mediating alum adjuvant activity. Furthermore, we propose that host DNA signaling differentially regulates IgE and IgG1 production after alum-adjuvanted immunization. We suggest that, on the one hand, host DNA induces primary B cell responses, including IgG1 production, through interferon response factor 3 (Irf3)-independent mechanisms. On the other hand, we suggest that host DNA also stimulates 'canonical' T helper type 2 (T(H)2) responses, associated with IgE isotype switching and peripheral effector responses, through Irf3-dependent mechanisms. The finding that host DNA released from dying cells acts as a damage-associated molecular pattern that mediates alum adjuvant activity may increase our understanding of the mechanisms of action of current vaccines and help in the design of new adjuvants.
authors.affiliation: Laboratory of Cellular and Molecular Physiology, Groupe Interdisciplinaire de Génoprotéomique Appliquée, University of Liège, Liège, Belgium.
authors.forename: Thomas
authors.initials: T
authors.lastname: Marichal
authors.forename: Keiichi
authors.initials: K
authors.lastname: Ohata
authors.forename: Denis
authors.initials: D
authors.lastname: Bedoret
authors.forename: Claire
authors.initials: C
authors.lastname: Mesnil
authors.forename: Catherine
authors.initials: C
authors.lastname: Sabatel
authors.forename: Kouji
authors.initials: K
authors.lastname: Kobiyama
authors.forename: Pierre
authors.initials: P
authors.lastname: Lekeux
authors.forename: Cevayir
authors.initials: C
authors.lastname: Coban
authors.forename: Shizuo
authors.initials: S
authors.lastname: Akira
authors.forename: Ken J
authors.initials: KJ
authors.lastname: Ishii
authors.forename: Fabrice
authors.initials: F
authors.lastname: Bureau
authors.forename: Christophe J
authors.initials: CJ
authors.lastname: Desmet
mesh_terms: D000276:Adjuvants, Immunologic / Q000378:metabolism* / Q000494:pharmacology; D000534:Alum Compounds / Q000494:pharmacology; D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology*; D016923:Cell Death / Q000187:drug effects; D004247:DNA / Q000378:metabolism*; D003850:Deoxyribonuclease I; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D006023:Glycoproteins / Q000235:genetics; D007073:Immunoglobulin E / Q000378:metabolism; D007074:Immunoglobulin G / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016601:RNA-Binding Proteins; D015398:Signal Transduction / Q000276:immunology*; D013053:Spectrophotometry; D018418:Th2 Cells / Q000276:immunology*; D051217:Toll-Like Receptor 9 / Q000235:genetics
chemical_list: D000276:Adjuvants, Immunologic; D000534:Alum Compounds; D006023:Glycoproteins; D007074:Immunoglobulin G; D016601:RNA-Binding Proteins; C495370:Tlr9 protein, mouse; D051217:Toll-Like Receptor 9; C402632:Zbp1 protein, mouse; C041524:aluminum sulfate; D007073:Immunoglobulin E; D004247:DNA; D003850:Deoxyribonuclease I