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International Immunology Advance Access originally published online on September 19, 2005
International Immunology 2005 17(11):1429-1438; doi:10.1093/intimm/dxh321
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© The Japanese Society for Immunology. 2005. All rights reserved. For permissions, please e-mail: journals.permissions@oupjournals.org

Ligand and cytokine dependence of the immunosuppressive pathway of tryptophan catabolism in plasmacytoid dendritic cells

Francesca Fallarino1, Ciriana Orabona1, Carmine Vacca1, Roberta Bianchi1, Stefania Gizzi1, Carine Asselin-Paturel2, Maria Cristina Fioretti1, Giorgio Trinchieri2, Ursula Grohmann1 and Paolo Puccetti1

1 Department of Experimental Medicine, Section of Pharmacology, University of Perugia, 06126 Perugia, Italy
2 Laboratory for Immunological Research, Schering-Plough Research Institute, 69571 Dardilly, France

Correspondence to: P. Puccetti; E-mail: plopcc{at}tin.it

Murine plasmacytoid dendritic cells (pDCs) have been credited with a unique ability to express indoleamine 2,3-dioxygenase (IDO) function and mediate immunosuppression in specific settings; yet, the conditions of spontaneous versus induced activity have remained unclear. We have used maneuvers known to up-regulate IDO in different cell types and have examined the relative efficacy and mechanisms of the induced activity in splenic pDCs, namely, after specific receptor engagement by CTLA-4-Ig, CD200-Ig or CD28-Ig, the latter in combination with silenced expression of the suppressor of cytokine signaling 3 (SOCS3) gene. We found that pDCs (CD11c+ mPDCA-1+ 120G8+) do not express IDO and are not tolerogenic under basal conditions. B7-1 engagement by CTLA-4-Ig, CD200R1 engagement by CD200-Ig and B7-1/B7-2 engagement by CD28-Ig in SOCS3-deficient pDCs were each capable of initiating IDO-dependent tolerance via different mechanisms. IFN-{gamma} was the major cytokine responsible for CTLA-4-Ig effects, and type I IFNs for those of CD200-Ig. Immunosuppression by CD28-Ig in the absence of SOCS3 required IFN-{gamma} induction and IFN-like actions of IL-6. Therefore, although pDCs do not mediate IDO-dependent tolerance constitutively, multiple ligands and cytokines will contribute to the expression of a tolerogenic phenotype by pDCs in the mouse.

Keywords: CD28-Ig, CD200-Ig, CTLA-4-Ig, plasmacytoid dendritic cells

Transmitting editor: K. M. Murphy


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