Carbomer-based adjuvant elicits CD8 T-cell immunity by inducing a distinct metabolic state in cross-presenting dendritic cells

• Type of Material: Article
• Authors: Woojong Lee, University of Wisconsin; Brock Kingstad-Bakke, University of Wisconsin; Brett Paulson, University of Wisconsin; Autum Larsen, University of Wisconsin; Katherine Overmyer, University of Wisconsin; Chandranaik B. Marinaik, University of Wisconsin; Kelly Dulli, University of Wisconsin; Randall Toy, Georgia Institute of Technology; Gabriela Vogel, Georgia Institute of Technology; Katherine P. Mueller, University of Wisconsin; Kelsey Tweed, University of Wisconsin; Alex J. Walsh, University of Wisconsin; Jason Russell, University of Wisconsin; Krishanu Saha, University of Wisconsin; Leticia Reyes, University of Wisconsin; Melissa C. Skala, University of Wisconsin; John-Demian Sauer, University of Wisconsin; Dmitry Shayakhmetov, Emory University; Joshua Coon, University of Wisconsin; Krishnendu Roy, Emory University; M. Suresh, University of Wisconsin
• Language: English
• Date: 2021-01-01
• Publisher: Public Library of Science
• Publication Version: Final Published Version
• Copyright Statement: © 2021 Lee et al.
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1371/journal.ppat.1009168
• Title of Journal or Parent Work: PLoS Pathogens
• Volume: 17
• Issue: 1
• Start Page: e1009168
• End Page: e1009168
• Grant/Funding Information: This project was supported in part by NIH P41 GM108538 (to J.C.), R01CA188034 (to J.D.S.), and S10 OD018039.; K.M. was supported by an NSF Graduate Research Fellowship (DGE-1747503), and K.S. was supported by NSF (EEC-1648035, CBET- 1645123) and NIH (3P30CA014520-45S6).; This work was supported by PHS grant U01 AI124299, R21 AI149793-01 and John E. Butler Professorship to M.S.;; K.T., A.J.W., and M.C.S. were supported by the NIH (R01 CA205101).; W.L. was supported by a predoctoral fellowship from the American Heart Association (18PRE34080150).
• Keywords: NADPH Oxidase; Polyunsaturated fatty acid; Glycolytic metabolism; Science & Technology; MHC class-1; Membrane organization; Virology; Vaccine; Inflammasome; Life Sciences & Biomedicine; Parasitology; Bacterial antigens; Activation; Microbiology; Antigen representation
• Research Categories: Engineering, Biomedical; Biology, Virology; Biology, Parasitology; Biology, Microbiology

Abstract

There is a critical need for adjuvants that can safely elicit potent and durable T cell-based immunity to intracellular pathogens. Here, we report that parenteral vaccination with a carbomer-based adjuvant, Adjuplex (ADJ), stimulated robust CD8 T-cell responses to subunit antigens and afforded effective immunity against respiratory challenge with a virus and a systemic intracellular bacterial infection. Studies to understand the metabolic and molecular basis for ADJ’s effect on antigen cross-presentation by dendritic cells (DCs) revealed several unique and distinctive mechanisms. ADJ-stimulated DCs produced IL-1β and IL-18, suggestive of inflammasome activation, but in vivo activation of CD8 T cells was unaffected in caspase 1-deficient mice. Cross-presentation induced by TLR agonists requires a critical switch to anabolic metabolism, but ADJ enhanced cross presentation without this metabolic switch in DCs. Instead, ADJ induced in DCs, an unique metabolic state, typified by dampened oxidative phosphorylation and basal levels of glycolysis. In the absence of increased glycolytic flux, ADJ modulated multiple steps in the cytosolic pathway of cross-presentation by enabling accumulation of degraded antigen, reducing endosomal acidity and promoting antigen localization to early endosomes. Further, by increasing ROS production and lipid peroxidation, ADJ promoted antigen escape from endosomes to the cytosol for degradation by proteasomes into peptides for MHC I loading by TAP-dependent pathways. Furthermore, we found that induction of lipid bodies (LBs) and alterations in LB composition mediated by ADJ were also critical for DC cross-presentation. Collectively, our model challenges the prevailing metabolic paradigm by suggesting that DCs can perform effective DC cross-presentation, independent of glycolysis to induce robust T cell-dependent protective immunity to intracellular pathogens. These findings have strong implications in the rational development of safe and effective immune adjuvants to potentiate robust T-cell based immunity.