title: Alum interaction with dendritic cell membrane lipids is essential for its adjuvanticity.
abstract: As an approved vaccine adjuvant for use in humans, alum has vast health implications, but, as it is a crystal, questions remain regarding its mechanism. Furthermore, little is known about the target cells, receptors, and signaling pathways engaged by alum. Here we report that, independent of inflammasome and membrane proteins, alum binds dendritic cell (DC) plasma membrane lipids with substantial force. Subsequent lipid sorting activates an abortive phagocytic response that leads to antigen uptake. Such activated DCs, without further association with alum, show high affinity and stable binding with CD4(+) T cells via the adhesion molecules intercellular adhesion molecule-1 (ICAM-1) and lymphocyte function-associated antigen-1 (LFA-1). We propose that alum triggers DC responses by altering membrane lipid structures. This study therefore suggests an unexpected mechanism for how this crystalline structure interacts with the immune system and how the DC plasma membrane may behave as a general sensor for solid structures.
authors.affiliation: Immunology Research Group, Department of Microbiology & Infectious Diseases, and Snyder Institute, University of Calgary, Calgary, Alberta, Canada.
authors.forename: Tracy L
authors.initials: TL
authors.lastname: Flach
authors.forename: Gilbert
authors.initials: G
authors.lastname: Ng
authors.forename: Aswin
authors.initials: A
authors.lastname: Hari
authors.forename: Melanie D
authors.initials: MD
authors.lastname: Desrosiers
authors.forename: Ping
authors.initials: P
authors.lastname: Zhang
authors.forename: Sandra M
authors.initials: SM
authors.lastname: Ward
authors.forename: Mark E
authors.initials: ME
authors.lastname: Seamone
authors.forename: Akosua
authors.initials: A
authors.lastname: Vilaysane
authors.forename: Ashley D
authors.initials: AD
authors.lastname: Mucsi
authors.forename: Yin
authors.initials: Y
authors.lastname: Fong
authors.forename: Elmar
authors.initials: E
authors.lastname: Prenner
authors.forename: Chang Chun
authors.initials: CC
authors.lastname: Ling
authors.forename: Jurg
authors.initials: J
authors.lastname: Tschopp
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Muruve
authors.forename: Matthias W
authors.initials: MW
authors.lastname: Amrein
authors.forename: Yan
authors.initials: Y
authors.lastname: Shi
mesh_terms: D000276:Adjuvants, Immunologic / Q000008:administration & dosage* / Q000493:pharmacokinetics; D000534:Alum Compounds / Q000008:administration & dosage* / Q000493:pharmacokinetics; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D002460:Cell Line; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism* / Q000648:ultrastructure; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D008563:Membrane Lipids / Q000276:immunology* / Q000378:metabolism*; D008855:Microscopy, Electron, Scanning; D018448:Models, Immunological; D010587:Phagocytosis / Q000187:drug effects; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology; D000072377:Syk Kinase; D014612:Vaccines / Q000008:administration & dosage
chemical_list: D000276:Adjuvants, Immunologic; D000534:Alum Compounds; D047908:Intracellular Signaling Peptides and Proteins; D008563:Membrane Lipids; D014612:Vaccines; C041524:aluminum sulfate; D019869:Phosphatidylinositol 3-Kinases; D011505:Protein-Tyrosine Kinases; C000606896:SYK protein, human; D000072377:Syk Kinase