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

• Published in: International immunology Vol. 17; no. 11; pp. 1429 - 1438
• Main Authors: Fallarino, Francesca, Orabona, Ciriana, Vacca, Carmine, Bianchi, Roberta, Gizzi, Stefania, Asselin-Paturel, Carine, Fioretti, Maria Cristina, Trinchieri, Giorgio, Grohmann, Ursula, Puccetti, Paolo
• Format: Journal Article
• Language: English
• Published: England Oxford University Press 01.11.2005; Oxford Publishing Limited (England)
• Subjects: 1-MT 1-methyl-D; 3-dioxygenase; Animals; Antigens, CD - genetics; Antigens, CD - immunology; CD200-Ig; CD28-Ig; CTLA-4-Ig; Cytokines - immunology; DC dendritic cell; Dendritic Cells - cytology; Dendritic Cells - enzymology; Dendritic Cells - immunology; IDO indoleamine 2; Immune Tolerance; Indoleamine-Pyrrole 2,3,-Dioxygenase - biosynthesis; Indoleamine-Pyrrole 2,3,-Dioxygenase - immunology; L-tryptophan; Ligands; Mice; Mice, Knockout; pDC plasmacytoid dendritic cell; Plasma Cells - cytology; Plasma Cells - enzymology; Plasma Cells - immunology; plasmacytoid dendritic cells; RT reverse transcription; siRNA small interfering RNA; SOCS suppressor of cytokine signaling; Tryptophan - immunology; Tryptophan - metabolism
• ISSN: 0953-8178; 1460-2377
• DOI: 10.1093/intimm/dxh321

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-γ 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-γ 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.