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-alpha) is the obligate inducer of IDO. We now report that IFN-alpha 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-alpha production by CD19(+) DC after B7 ligation. In contrast, IDO ablation did not block IFN-alpha production by CD19(+) DC after TLR9 ligation. IDO-mediated control of IFN-alpha production depended on tryptophan depletion as adding excess tryptophan also blocked IFN-alpha 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-alpha following B7 ligation, but produced IFN-alpha after TLR9 ligation. Thus, B7 and TLR9 ligands stimulate IFN-alpha expression in CD19(+) DC via distinct signaling pathways. In the case of B7 ligation, IDO activates cell-autonomous signals essential for IFN-alpha production, most likely by activating the GCN2-kinase-dependent stress response.
Manlapat
Anna K
AK
Immunotherapy and Cancer Centers, Department of Medicine, Medical College of Georgia, Augusta, GA 30912, USA.
Kahler
David J
DJ
Chandler
Phillip R
PR
Munn
David H
DH
Mellor
Andrew L
AL
D000818:Animals; D018941:Antigens, CD19 / Q000096:biosynthesis*; D003713:Dendritic Cells / Q000201:enzymology* / Q000276:immunology / Q000378:metabolism; D005786:Gene Expression Regulation / Q000502:physiology*; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D016898:Interferon-alpha / Q000096:biosynthesis / Q000235:genetics*; D051379:Mice; D008808:Mice, Inbred CBA; D018345:Mice, Knockout; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology
D018941:Antigens, CD19; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D016898:Interferon-alpha