Effective Combination Adjuvants Engage Both TLR and Inflammasome Pathways To Promote Potent Adaptive Immune Responses
| Autor: | Natasha Dubois Cauwelaert, Christopher B. Fox, Mark T. Orr, Darrick Carter, Nicholas D. Rintala, Ryan M. Kramer, Hong Liang, Emilie Seydoux, Michelle Archer |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Inflammasomes medicine.medical_treatment Interleukin-1beta Mice 0302 clinical medicine Adenosine Triphosphate Glucosides Immunology and Allergy Mice Knockout B-Lymphocytes Vaccines Chemistry Vaccination Inflammasome Acquired immune system Cell biology medicine.anatomical_structure Lipid A lipids (amino acids peptides and proteins) Female Adjuvant medicine.drug Squalene T cell Immunology Article 03 medical and health sciences Interferon-gamma Immune system Adjuvants Immunologic Immunity NLR Family Pyrin Domain-Containing 3 Protein medicine Animals Antigens B cell Receptors Interleukin-1 Type I Tumor Necrosis Factor-alpha Interferon-beta Th1 Cells Immunity Humoral CARD Signaling Adaptor Proteins Mice Inbred C57BL Toll-Like Receptor 4 Adaptor Proteins Vesicular Transport 030104 developmental biology Myeloid Differentiation Factor 88 TLR4 Interleukin-2 030215 immunology |
| Zdroj: | Journal of immunology (Baltimore, Md. : 1950). 201(1) |
| ISSN: | 1550-6606 |
| Popis: | The involvement of innate receptors that recognize pathogen- and danger-associated molecular patterns is critical to programming an effective adaptive immune response to vaccination. The synthetic TLR4 agonist glucopyranosyl lipid adjuvant (GLA) synergizes with the squalene oil-in-water emulsion (SE) formulation to induce strong adaptive responses. Although TLR4 signaling through MyD88 and TIR domain–containing adapter inducing IFN-β are essential for GLA-SE activity, the mechanisms underlying the synergistic activity of GLA and SE are not fully understood. In this article, we demonstrate that the inflammasome activation and the subsequent release of IL-1β are central effectors of the action of GLA-SE, as infiltration of innate cells into the draining lymph nodes and production of IFN-γ are reduced in ASC−/− animals. Importantly, the early proliferation of Ag-specific CD4+ T cells was completely ablated after immunization in ASC−/− animals. Moreover, numbers of Ag-specific CD4+ T and B cells as well as production of IFN-γ, TNF-α, and IL-2 and Ab titers were considerably reduced in ASC−/−, NLRP3−/−, and IL-1R−/− mice compared with wild-type mice and were completely ablated in TLR4−/− animals. Also, extracellular ATP, a known trigger of the inflammasome, augments Ag-specific CD4+ T cell responses, as hydrolyzing it with apyrase diminished adaptive responses induced by GLA-SE. These data thus demonstrate that GLA-SE adjuvanticity acts through TLR4 signaling and NLRP3 inflammasome activation to promote robust Th1 and B cell responses to vaccine Ags. The findings suggest that engagement of both TLR and inflammasome activators may be a general paradigm for induction of robust CD4 T cell immunity with combination adjuvants such as GLA-SE. |
| Databáze: | OpenAIRE |
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