title: IL-18 and Subcapsular Lymph Node Macrophages are Essential for Enhanced B Cell Responses with TLR4 Agonist Adjuvants.
abstract: Designing modern vaccine adjuvants depends on understanding the cellular and molecular events that connect innate and adaptive immune responses. The synthetic TLR4 agonist glycopyranosyl lipid adjuvant (GLA) formulated in a squalene-in-water emulsion (GLA-SE) augments both cellular and humoral immune responses to vaccine Ags. This adjuvant is currently included in several vaccines undergoing clinical evaluation including those for tuberculosis, leishmaniasis, and influenza. Delineation of the mechanisms of adjuvant activity will enable more informative evaluation of clinical trials. Early after injection, GLA-SE induces substantially more Ag-specific B cells, higher serum Ab titers, and greater numbers of T follicular helper (TFH) and Th1 cells than alum, the SE alone, or GLA without SE. GLA-SE augments Ag-specific B cell differentiation into germinal center and memory precursor B cells as well as preplasmablasts that rapidly secrete Abs. CD169+SIGNR1+subcapsular medullary macrophages are the primary cells to take up GLA-SE after immunization and are critical for the innate immune responses, including rapid IL-18 production, induced by GLA-SE. Depletion of subcapsular macrophages (SCMф) or abrogation of IL-18 signaling dramatically impairs the Ag-specific B cell and Ab responses augmented by GLA-SE. Depletion of SCMф also drastically reduces the Th1 but not the TFHresponse. Thus the GLA-SE adjuvant operates through interaction with IL-18-producing SCMф for the rapid induction of B cell expansion and differentiation, Ab secretion, and Th1 responses, whereas augmentation of TFHnumbers by GLA-SE is independent of SCMф.
authors: Infectious Disease Research Institute, Seattle, WA 98102.
authors: Anthony L
authors: AL
authors: Desbien
authors: Infectious Disease Research Institute, Seattle, WA 98102.
authors: Natasha
authors: 0000-0003-4895-9117
authors: N
authors: Dubois Cauwelaert
authors: Infectious Disease Research Institute, Seattle, WA 98102.
authors: Steven J
authors: SJ
authors: Reed
authors: Infectious Disease Research Institute, Seattle, WA 98102.
authors: Hilton R
authors: HR
authors: Bailor
authors: Infectious Disease Research Institute, Seattle, WA 98102.
authors: Hong
authors: 0000-0003-0940-7723
authors: H
authors: Liang
authors: Infectious Disease Research Institute, Seattle, WA 98102.|Department of Global Health, University of Washington, Seattle, WA 98195; and.|PAI Life Sciences, Seattle, WA 98102.
authors: Darrick
authors: 0000-0001-5901-3402
authors: D
authors: Carter
authors: Infectious Disease Research Institute, Seattle, WA 98102.|Department of Global Health, University of Washington, Seattle, WA 98195; and.
authors: Malcolm S
authors: MS
authors: Duthie
authors: Infectious Disease Research Institute, Seattle, WA 98102.|Department of Global Health, University of Washington, Seattle, WA 98195; and.
authors: Christopher B
authors: CB
authors: Fox
authors: Infectious Disease Research Institute, Seattle, WA 98102.|Department of Global Health, University of Washington, Seattle, WA 98195; and.
authors: Steven G
authors: SG
authors: Reed
authors: Infectious Disease Research Institute, Seattle, WA 98102; mark.orr@idri.org.|Department of Global Health, University of Washington, Seattle, WA 98195; and.
authors: Mark T
authors: 0000-0003-2684-4722
authors: MT
authors: Orr
mesh_terms: D000276:Adjuvants, Immunologic / Q000494:pharmacology*; D000818:Animals; D001402:B-Lymphocytes / Q000166:cytology / Q000276:immunology*; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000276:immunology; D002454:Cell Differentiation / Q000187:drug effects* / Q000276:immunology; D005260:Female; D005960:Glucosides / Q000493:pharmacokinetics / Q000494:pharmacology*; D020382:Interleukin-18 / Q000235:genetics / Q000276:immunology*; D053727:Interleukin-18 Receptor alpha Subunit / Q000235:genetics / Q000276:immunology; D037181:Lectins, C-Type / Q000235:genetics / Q000276:immunology; D008050:Lipid A / Q000493:pharmacokinetics / Q000494:pharmacology*; D008198:Lymph Nodes / Q000166:cytology / Q000276:immunology*; D008264:Macrophages / Q000166:cytology / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D011956:Receptors, Cell Surface / Q000235:genetics / Q000276:immunology; D063267:Sialic Acid Binding Ig-like Lectin 1 / Q000235:genetics / Q000276:immunology; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D018417:Th1 Cells / Q000166:cytology / Q000276:immunology; D051197:Toll-Like Receptor 4 / Q000819:agonists* / Q000235:genetics / Q000276:immunology; D000099215:DC-Specific ICAM-3 Grabbing Nonintegrin
chemical_list: D000276:Adjuvants, Immunologic; D015815:Cell Adhesion Molecules; D005960:Glucosides; D020382:Interleukin-18; D053727:Interleukin-18 Receptor alpha Subunit; D037181:Lectins, C-Type; D008050:Lipid A; D011956:Receptors, Cell Surface; D063267:Sialic Acid Binding Ig-like Lectin 1; D051197:Toll-Like Receptor 4; D000099215:DC-Specific ICAM-3 Grabbing Nonintegrin; C508573:Il18r1 protein, mouse; C571167:Siglec1 protein, mouse; C493487:Tlr4 protein, mouse; C000608161:glucopyranosyl lipid-A