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International Immunology Advance Access published online on September 19, 2005
International Immunology, 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
Received June 6, 2005
Accepted August 18, 2005

Article

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

Francesca Fallarino 1, Ciriana Orabona 1, Carmine Vacca 1, Roberta Bianchi 1, Stefania Gizzi 1, Carine Asselin-Paturel 2, Maria Cristina Fioretti 1, Giorgio Trinchieri 2, Ursula Grohmann 1, and Paolo Puccetti 1*

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

* To whom correspondence should be addressed.
Paolo Puccetti, E-mail: plopcc{at}tin.it


  Abstract

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.
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