Muñoz-Wolf and Ward et al. investigated the physicochemical properties and mechanism of action of polymeric nanoparticles for use as vaccine adjuvants to generate cell-mediated immunity. Polystyrene- and PLGA-based nanoparticle adjuvants were only effective if ~50 nm in size, triggering regulated immunogenic cell death, and outperformed molecular adjuvants (CpG and 2’3’cGAMP). Induction of ROS in dying cells activated non-canonical caspase-11 inflammasomes, gasdermin cleavage, pore formation, and release of the critical inflammatory mediators IL-1β and IL-18, which served complementary roles in CD8+ T cell induction.
Contributed by Ed Fritsch
ABSTRACT: The non-canonical inflammasome sensor caspase-11 and gasdermin D (GSDMD) drive inflammation and pyroptosis, a type of immunogenic cell death that favors cell-mediated immunity (CMI) in cancer, infection, and autoimmunity. Here we show that caspase-11 and GSDMD are required for CD8(+) and Th1 responses induced by nanoparticulate vaccine adjuvants. We demonstrate that nanoparticle-induced reactive oxygen species (ROS) are size dependent and essential for CMI, and we identify 50- to 60-nm nanoparticles as optimal inducers of ROS, GSDMD activation, and Th1 and CD8(+) responses. We reveal a division of labor for IL-1 and IL-18, where IL-1 supports Th1 and IL-18 promotes CD8(+) responses. Exploiting size as a key attribute, we demonstrate that biodegradable poly-lactic co-glycolic acid nanoparticles are potent CMI-inducing adjuvants. Our work implicates ROS and the non-canonical inflammasome in the mode of action of polymeric nanoparticulate adjuvants and establishes adjuvant size as a key design principle for vaccines against cancer and intracellular pathogens.
Author Info: (1) Adjuvant Research Group, School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2 D02 R590, Ireland; Translational & Respi
Author Info: (1) Adjuvant Research Group, School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2 D02 R590, Ireland; Translational & Respiratory Immunology Lab, Department of Clinical Medicine, School of Medicine, Trinity Biomedical Sciences Institute, Dublin D02 R590, Ireland; Clinical Medicine Tallaght University Hospital, Dublin D24 NR04, Ireland. (2) Adjuvant Research Group, School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2 D02 R590, Ireland. (3) Adjuvant Research Group, School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2 D02 R590, Ireland. (4) Adjuvant Research Group, School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2 D02 R590, Ireland. (5) Department of Microbiology, Moyne Institute of Preventive Medicine, School of Genetics and Microbiology, Trinity College Dublin, Dublin, Ireland; Institute of Microbiology and Infection, College of Medical and Dental Sciences, University of Birmingham, Birmingham B15 2TT, UK. (6) Adjuvant Research Group, School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2 D02 R590, Ireland. (7) Adjuvant Research Group, School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2 D02 R590, Ireland. (8) School of Biochemistry and Immunology, Trinity Biomedical Science Institute (TBSI), Trinity College Dublin, Dublin D02 R590, Ireland. (9) School of Biochemistry and Immunology, Trinity Biomedical Science Institute (TBSI), Trinity College Dublin, Dublin D02 R590, Ireland. (10) School of Biochemistry and Immunology, Trinity Biomedical Science Institute (TBSI), Trinity College Dublin, Dublin D02 R590, Ireland. (11) Smurfit Institute of Genetics, School of Genetics and Microbiology, Trinity College Dublin, Dublin, Ireland. (12) Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow G4 0RE, UK. (13) Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow G4 0RE, UK. (14) Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow G4 0RE, UK. (15) Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow G4 0RE, UK. (16) School of Biochemistry and Immunology, Trinity Biomedical Science Institute (TBSI), Trinity College Dublin, Dublin D02 R590, Ireland. (17) Adjuvant Research Group, School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2 D02 R590, Ireland; Centre for Research on Adaptive Nanostructures and Nanodevices (CRANN) & Advanced Materials Bio-Engineering Research Centre (AMBER), Trinity College Dublin, Dublin D02 PN40, Ireland. Electronic address: lavellee@tcd.ie.
