The Adjuvant Combination of dmLT and Monophosphoryl Lipid A Activates the Canonical, Nonpyroptotic NLRP3 Inflammasome in Dendritic Cells and Significantly Interacts to Expand Antigen-Specific CD4 T Cells
Author:
Bauer David L.1ORCID,
Bachnak Louay1ORCID,
Limbert Vanessa M.1,
Horowitz Rebecca M.1ORCID,
Baudier Robin L.2ORCID,
D’Souza Shaina J.1ORCID,
Immethun Victoria E.1,
Kurtz Jonathan R1,
Grant Samuel B.1,
McLachlan James B.1ORCID
Affiliation:
1. *Department of Microbiology and Immunology, Tulane University School of Medicine, New Orleans, LA
2. †Department of Epidemiology, Tulane School of Public Health and Tropical Medicine, New Orleans, LA
Abstract
Abstract
Adjuvants are often essential additions to vaccines that enhance the activation of innate immune cells, leading to more potent and protective T and B cell responses. Only a few vaccine adjuvants are currently used in approved vaccine formulations in the United States. Combinations of one or more adjuvants have the potential to increase the efficacy of existing and next-generation vaccines. In this study, we investigated how the nontoxic double mutant Escherichia coli heat-labile toxin R192G/L211A (dmLT), when combined with the TLR4 agonist monophosphoryl lipid A (MPL-A), impacted innate and adaptive immune responses to vaccination in mice. We found that the combination of dmLT and MPL-A induced an expansion of Ag-specific, multifaceted Th1/2/17 CD4 T cells higher than that explained by adding responses to either adjuvant alone. Furthermore, we observed more robust activation of primary mouse bone marrow–derived dendritic cells in the combination adjuvant–treated group via engagement of the canonical NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome complex. This was marked by a multiplicative increase in the secretion of active IL-1β that was independent of classical gasdermin D–mediated pyroptosis. Moreover, the combination adjuvant increased the production of the secondary messengers cAMP and PGE2 in dendritic cells. These results demonstrate how certain adjuvant combinations could be used to potentiate better vaccine responses to combat a variety of pathogens.
Funder
HHS | NIH | National Institute of Allergy and Infectious Diseases
Publisher
The American Association of Immunologists
Subject
Immunology,Immunology and Allergy
Reference60 articles.
1. Global burden of infectious diseases;Michaud;Encyclopedia of Microbiology,2009
2. Standing up to infectious disease;Nat. Microbiol.,2019
3. The Global Enteric Multicenter Study (GEMS): impetus, rationale, and genesis;Levine;Clin. Infect. Dis.,2012
4. Vaccine impact: benefits for human health;Doherty;Vaccine,2016
5. Recent advances in vaccine technologies;Francis;Vet. Clin. North Am. Small Anim. Pract.,2018
Cited by
1 articles.
订阅此论文施引文献
订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献