Carbomer-Based Adjuvant Elicits Cd8 T-Cell Immunity By Inducing A Distinct Metabolic State In Cross-Presenting Dendritic Cells

PLOS PATHOGENS(2021)

引用 17|浏览30
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摘要
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-1 beta 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.Author summaryAn adjuvant is the pharmacological agent that is added to vaccines to boost immune responses. Currently, there are only seven FDA-approved adjuvants for human use, and vaccines based on these adjuvants have mainly been evaluated for elicitation of antibody-based immunity. However, vaccines need to also stimulate T cell-mediated immunity to protect against diseases such as AIDS, TB and Malaria. Hence, there is a critical need to develop adjuvants that stimulate protective T cell immunity. Here, we identified an adjuvant (Adjuplex; ADJ) that safely induces strong T cell immunity and protects against virus and intracellular bacteria. We also found that ADJ stimulated T cell immunity by unique mechanisms that did not include metabolic activation of antigen-presenting dendritic cells. Instead, ADJ induced a low metabolic state and engaged mechanisms including lipid pathways and induction of reactive oxygen species to promote activation of T cells by dendritic cells, following vaccination. These data not only provide new mechanistic insights into the mechanisms driving activation of T cells by ADJ, it provides a blue print for what adjuvants need to do to induce protection against infections that require T cell immunity.
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