title: Inflammasome-dependent and -independent IL-18 production mediates immunity to the ISCOMATRIX adjuvant.
abstract: Adjuvants are an essential component of modern vaccines and used for their ability to elicit immunity to coadministered Ags. Many adjuvants in clinical development are particulates, but how they drive innate and adaptive immune responses remains poorly understood. Studies have shown that a number of vaccine adjuvants activate inflammasome pathways in isolated APCs. However, the contribution of inflammasome activation to vaccine-mediated immunity in vivo remains controversial. In this study, we evaluated immune cell responses to the ISCOMATRIX adjuvant (IMX) in mice. Like other particulate vaccine adjuvants, IMX potently activated the NALP-3-ASC-Caspase-1 inflammasome in APCs, leading to IL-1β and IL-18 production. The IL-18R pathway, but not IL-1R, was required for early innate and subsequent cellular immune responses to a model IMX vaccine. APCs directly exposed to IMX underwent an endosome-mediated cell-death response, which we propose initiates inflammatory events locally at the injection site. Importantly, both inflammasome-related and -unrelated pathways contributed to IL-18 dependence in vivo following IMX administration. TNF-α provided a physiological priming signal for inflammasome-dependent IL-18 production by APCs, which correlated with reduced vaccine-mediated immune cell responses in TNF-α- or TNFR-deficient mice. Taken together, our findings highlight an important disconnect between the mechanisms of vaccine adjuvant action in vitro versus in vivo.
authors.affiliation: Cancer Immunology, Genentech, Inc., South San Francisco, CA 94080;
authors.forename: Nicholas S
authors.initials: NS
authors.lastname: Wilson
authors.forename: Peter
authors.initials: P
authors.lastname: Duewell
authors.forename: Becky
authors.initials: B
authors.lastname: Yang
authors.forename: Yun
authors.initials: Y
authors.lastname: Li
authors.forename: Scot
authors.initials: S
authors.lastname: Marsters
authors.forename: Sandra
authors.initials: S
authors.lastname: Koernig
authors.forename: Eicke
authors.initials: E
authors.lastname: Latz
authors.forename: Eugene
authors.initials: E
authors.lastname: Maraskovsky
authors.forename: Adriana Baz
authors.initials: AB
authors.lastname: Morelli
authors.forename: Max
authors.initials: M
authors.lastname: Schnurr
authors.forename: Avi
authors.initials: A
authors.lastname: Ashkenazi
mesh_terms: D000255:Adenosine Triphosphate / Q000276:immunology / Q000378:metabolism; D000276:Adjuvants, Immunologic / Q000494:pharmacology; D000818:Animals; D000938:Antigen-Presenting Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D015153:Blotting, Western; D002470:Cell Survival / Q000187:drug effects / Q000276:immunology; D002784:Cholesterol / Q000276:immunology* / Q000494:pharmacology; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D004338:Drug Combinations; D006801:Humans; D007109:Immunity / Q000187:drug effects / Q000276:immunology*; D058847:Inflammasomes / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D020382:Interleukin-18 / Q000276:immunology* / Q000378:metabolism; D053583:Interleukin-1beta / Q000276:immunology / Q000378:metabolism; D007694:Killer Cells, Natural / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology; D008247:Lysosomes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D017737:Macrophages, Peritoneal / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018613:Microscopy, Confocal; D010743:Phospholipids / Q000276:immunology* / Q000494:pharmacology; D018124:Receptors, Tumor Necrosis Factor / Q000172:deficiency / Q000235:genetics / Q000276:immunology; D012503:Saponins / Q000276:immunology* / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000172:deficiency / Q000235:genetics / Q000276:immunology
chemical_list: D000276:Adjuvants, Immunologic; D004338:Drug Combinations; C587672:IL1B protein, mouse; C493786:ISCOMATRIX; D058847:Inflammasomes; D020382:Interleukin-18; D053583:Interleukin-1beta; D010743:Phospholipids; D018124:Receptors, Tumor Necrosis Factor; D012503:Saponins; D014409:Tumor Necrosis Factor-alpha; D000255:Adenosine Triphosphate; D002784:Cholesterol