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

Anna K. Manlapat, David J. Kahler, Phillip R. Chandler, David H. Munn, Andrew L. Mellor

Research output: Contribution to journalArticle

65 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1064-1071
Number of pages8
JournalEuropean Journal of Immunology
Volume37
Issue number4
DOIs
StatePublished - Apr 1 2007

Fingerprint

Indoleamine-Pyrrole 2,3,-Dioxygenase
Interferon Type I
Dendritic Cells
Ligation
Tryptophan
Phosphotransferases
Regulatory T-Lymphocytes
Ligands
Amino Acids

Keywords

  • Dendritic cells
  • Immunoregulation
  • Indoleamine 2,3-dioxygenase
  • Interferon

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

Cell-autonomous control of interferon type I expression by indoleamine 2, 3-dioxygenase in regulatory CD19 + dendritic cells. / Manlapat, Anna K.; Kahler, David J.; Chandler, Phillip R.; Munn, David H.; Mellor, Andrew L.

In: European Journal of Immunology, Vol. 37, No. 4, 01.04.2007, p. 1064-1071.

Research output: Contribution to journalArticle

Manlapat, Anna K. ; Kahler, David J. ; Chandler, Phillip R. ; Munn, David H. ; Mellor, Andrew L. / Cell-autonomous control of interferon type I expression by indoleamine 2, 3-dioxygenase in regulatory CD19 + dendritic cells. In: European Journal of Immunology. 2007 ; Vol. 37, No. 4. pp. 1064-1071.
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