Direct Type I IFN but Not MDA5/TLR3 Activation of Dendritic Cells Is Required for Maturation and Metabolic Shift to Glycolysis after Poly IC Stimulation

Abstract

Type I IFN signaling is indispensable for the maturation of dendritic cells (DCs) that are required to elicit an immune response, and it also controls a shift in cellular metabolism to meet the increased energy demands of DC maturation.

Abstract

Type I interferons (IFNs) play an important role in direct antiviral defense as well as linking the innate and adaptive immune responses. On dendritic cells (DCs), IFNs facilitate their activation and contribute to CD8 ⁺ and CD4 ⁺ T cell priming. However, the precise molecular mechanism by which IFNs regulate maturation and immunogenicity of DCs in vivo has not been studied in depth. Here we show that, after in vivo stimulation with the TLR ligand poly IC, IFNs dominate transcriptional changes in DCs. In contrast to direct TLR3/mda5 signaling, IFNs are required for upregulation of all pathways associated with DC immunogenicity. In addition, metabolic pathways, particularly the switch from oxidative phosphorylation to glycolysis, are also regulated by IFNs and required for DC maturation. These data provide evidence for a metabolic reprogramming concomitant with DC maturation and offer a novel mechanism by which IFNs modulate DC maturation.

Author Summary

Immune responses are orchestrated by a specialized cell type called dendritic cells (DCs). In order to achieve durable and robust immunity, DCs need to undergo an intricate differentiation process known as maturation. This process is poorly understood at the moment. Poly IC, which mimics viral RNA and is an agonist for the viral pattern recognition receptors (PRRs) that signal “danger” to the immune system, can induce full maturation of DCs and it has been shown that this requires type I IFN signaling. In this study we set out to examine the specific signals provided by direct PRR or IFN stimulation that are required for DC maturation. We found to our surprise that type I IFN can regulate almost all steps of the DC's maturation process without requiring direct PRR involvement. We also show that type I IFN regulates several metabolic switches essential for preservation of DC integrity: it stimulates the expression of the hypoxia-inducible factor 1α (Hif1α), which controls the metabolic shift from oxidative phosphorylation (used by resting cells to generate energy) to aerobic glycolysis, a less efficient but faster energy-producing process. This metabolic shift was required to meet increased energy demands of activated DCs and to prevent their premature death, thus sustaining an immune response to viral infection.