Journal
EUROPEAN JOURNAL OF IMMUNOLOGY
Volume 37, Issue 4, Pages 1064-1071Publisher
WILEY
DOI: 10.1002/eji.200636690
Keywords
dendritic cells; immunoregulation; indoleamine 2,3-dioxygenase; interferon
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Funding
- NCI NIH HHS [CA096651, CA103320] Funding Source: Medline
- NIAID NIH HHS [AI063402] Funding Source: Medline
- NICHD NIH HHS [HD41187] Funding Source: Medline
- EUNICE KENNEDY SHRIVER NATIONAL INSTITUTE OF CHILD HEALTH &HUMAN DEVELOPMENT [R01HD041187] Funding Source: NIH RePORTER
- NATIONAL CANCER INSTITUTE [R01CA096651, R01CA103320] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES [R01AI063402] Funding Source: NIH RePORTER
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Following CD80/86 (137) 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 137 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 137 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 137 ligation, but produced IFN-alpha after TLR9 ligation. Thus, 137 and TLR9 ligands stimulate IFN-alpha expression in CD19(+) DC via distinct signaling pathways. In the case of 137 ligation, IDO activates cell-autonomous signals essential for IFN-alpha production, most likely by activating the GCN2-kinase-dependent stress response.
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