| First Author | Seydoux E | Year | 2018 |
| Journal | J Immunol | Volume | 201 |
| Issue | 1 | Pages | 98-112 |
| PubMed ID | 29769270 | Mgi Jnum | J:263325 |
| Mgi Id | MGI:6164066 | Doi | 10.4049/jimmunol.1701604 |
| Citation | Seydoux E, et al. (2018) Effective Combination Adjuvants Engage Both TLR and Inflammasome Pathways To Promote Potent Adaptive Immune Responses. J Immunol 201(1):98-112 |
| abstractText | 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-beta 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-1beta are central effectors of the action of GLA-SE, as infiltration of innate cells into the draining lymph nodes and production of IFN-gamma 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-gamma, TNF-alpha, 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. |
