IL-18 and Subcapsular Lymph Node Macrophages are Essential for Enhanced B Cell Responses with TLR4 Agonist Adjuvants
| Autor: | Anthony L. Desbien, Darrick Carter, Christopher B. Fox, Hilton R. Bailor, Steven G. Reed, Hong Liang, Mark T. Orr, Malcolm S. Duthie, Steven J. Reed, Natasha Dubois Cauwelaert |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Sialic Acid Binding Ig-like Lectin 1 medicine.medical_treatment Immunology Receptors Cell Surface Biology Article Mice 03 medical and health sciences 0302 clinical medicine Immune system Adjuvants Immunologic Glucosides medicine Animals Immunology and Allergy Lectins C-Type Lymph node B cell Mice Knockout B-Lymphocytes Innate immune system Macrophages Interleukin-18 nutritional and metabolic diseases Germinal center Cell Differentiation Th1 Cells Toll-Like Receptor 4 Lipid A 030104 developmental biology medicine.anatomical_structure Immunization TLR4 Female lipids (amino acids peptides and proteins) Lymph Nodes Cell Adhesion Molecules Interleukin-18 Receptor alpha Subunit Adjuvant Signal Transduction 030215 immunology |
| Zdroj: | The Journal of Immunology. 197:4351-4359 |
| ISSN: | 1550-6606 0022-1767 |
| DOI: | 10.4049/jimmunol.1600993 |
| Popis: | 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 TFH response. 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 TFH numbers by GLA-SE is independent of SCMф. |
| Databáze: | OpenAIRE |
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