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Cell‐autonomous control of interferon type I expression by indoleamine 2,3‐dioxygenase in regulatory CD19+ dendritic cells

Following CD80/86 (B7) and TLR9 ligation, small subsets of splenic dendritic cells expressing CD19 (CD19+ DC) acquire potent T cell regulatory functions due to induced expression of the intracellular enzyme indoleamine 2,3‐dioxygenase (IDO), which catabolizes tryptophan. In CD19+ DC, IFN type I (IFN‐α) is the obligate inducer of IDO. We now report that IFN‐α production needed to stimulate high‐level expression of IDO following B7 ligation is itself dependent on basal levels of IDO activity. Genetic and pharmacologic ablation of IDO completely abrogated IFN‐α production by CD19+ DC after B7 ligation. In contrast, IDO ablation did not block IFN‐α production by CD19+ DC after TLR9 ligation. IDO‐mediated control of IFN‐α production depended on tryptophan depletion as adding excess tryptophan also blocked IFN‐α expression after B7 ligation. Consistent with this, DC from mice deficient in general control of non‐derepressible‐2 (GCN2)‐kinase, a component of the cellular stress response to amino acid withdrawal, did not produce IFN‐α following B7 ligation, but produced IFN‐α after TLR9 ligation. Thus, B7 and TLR9 ligands stimulate IFN‐α expression in CD19+ DC via distinct signaling pathways. In the case of B7 ligation, IDO activates cell‐autonomous signals essential for IFN‐α production, most likely by activating the GCN2‐kinase‐dependent stress response.