Recent advances reveal that metabolic reprogramming is required for adequate antiviral
responses of dendritic cells (DCs) that possess the capacity to initiate innate and adaptive
immune responses. Several reports indicate that Toll-like receptor (TLR) stimulation
of DCs is accompanied by a rapid induction of glycolysis; however, the metabolic
requirements of retinoic-acid inducible gene I (RIG-I)-like receptor (RLR) activation have
not defined either in conventional DCs (cDCs) or in plasmacytoid DCs (pDCs) that are
the major producers of type I interferons (IFN) upon viral infections. To sense viruses
and trigger an early type I IFN response, pDCs rely on endosomal TLRs, whereas cDCs
employ cytosolic RIG-I, which is constitutively present in their cytoplasm. We previously
found that RIG-I is upregulated in pDCs upon endosomal TLR activation and contributes
to the late phase of type I IFN responses. Here we report that TLR9-driven activation
of human pDCs leads to a metabolic transition to glycolysis supporting the production
of type I IFNs, whereas RIG-I-mediated antiviral responses of pDCs do not require
glycolysis and rather rely on oxidative phosphorylation (OXPHOS) activity. In particular,
TLR9-activated pDCs show increased extracellular acidification rate (ECAR), lactate
production, and upregulation of key glycolytic genes indicating an elevation in glycolytic
flux. Furthermore, administration of 2-deoxy-D-glucose (2-DG), an inhibitor of glycolysis,
significantly impairs the TLR9-induced secretion of type I IFNs by human pDCs. In
contrast, RIG-I stimulation of pDCs does not result in any alterations of ECAR, and type I
IFN production is not inhibited but rather promoted by 2-DG treatment. Moreover, pDCs
activated via TLR9 but not RIG-I in the presence of 2-DG are impaired in their capacity to
prime allogeneic naïve CD8+ T cell proliferation. Interestingly, human monocyte-derived
DCs (moDC) triggered via RIG-I show a commitment to glycolysis to promote type I IFN
production and T cell priming in contrast to pDCs. Our findings reveal for the first time, that
pDCs display a unique metabolic profile; TLR9-driven but not RIG-I-mediated activation
of pDCs requires glycolytic reprogramming. Nevertheless, the metabolic signature of
RIG-I-stimulated moDCs is characterized by glycolysis suggesting that RIG-I-induced
metabolic alterations are rather cell type-specific and not receptor-specific