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International Immunology Advance Access originally published online on June 20, 2005
International Immunology 2005 17(7):909-919; doi:10.1093/intimm/dxh271
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© The Japanese Society for Immunology. 2005. All rights reserved. For permissions, please e-mail: journals.permissions@oupjournals.org

A minor population of splenic dendritic cells expressing CD19 mediates IDO-dependent T cell suppression via type I IFN signaling following B7 ligation

Babak Baban1,*, Anna M. Hansen1,*, Phillip R. Chandler1,2, Anna Manlapat1, Adam Bingaman1,3, David J. Kahler1, David H. Munn1,4 and Andrew L. Mellor1,2

1 Immunotherapy Center and 2 Department of Medicine, 3 Department of Surgery and 4 Department of Pediatrics, Medical College of Georgia, 1120, 15th Street, Augusta, GA 30912, USA

Correspondence to: A. L. Mellor; E-mail: amellor{at}mcg.edu

By ligating CD80/CD86 (B7) molecules, the synthetic immunomodulatory reagent CTLA4-Ig (soluble synthetic CTLA4 fusion protein) induces expression of the enzyme indoleamine 2,3-dioxygenase (IDO) in some dendritic cells (DCs), which acquire potent T cell regulatory functions as a consequence. Here we show that this response occurred exclusively in a population of splenic DCs co-expressing the marker CD19. B7 ligation induced activation of the transcription factor signal transducer and activator of transcription (STAT1) in sorted CD19+, but not CD19NEG, DCs. STAT1 activation occurred even when DCs lacked receptors for type II IFN (IFN{gamma}); however, STAT1 activation and IDO up-regulation were not observed when DCs lacked receptors for type I IFN (IFN{alpha}ß). Thus, IFN{alpha}, but not IFN{gamma}, signaling was essential for STAT1 activation and IDO up-regulation in CD19+ DCs following B7 ligation. Consistent with these findings, B7 ligation also induced sorted CD19+, but not CD19NEG, DCs to express IFN{alpha}. Moreover, recombinant IFN{alpha} induced CD19+, but not CD19NEG, DCs to mediate IDO-dependent T cell suppression, showing that IFN{alpha} signaling could substitute for upstream signals from B7. These data reveal that a minor population of splenic DCs expressing the CD19 marker is uniquely responsive to B7 ligation, and that IFN{alpha}-mediated STAT1 activation is an essential intermediary signaling pathway that promotes IDO induction in these DCs. Thus, CD19+ DCs may be a target for regulatory T cells expressing surface CTLA4, and may suppress T cell responses via induction of IDO.

Keywords: CTLA4-Ig, dendritic cells, interferon, STAT1, T cell suppression

* These authors contributed equally to this study.

Transmitting editor: E. Simpson


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