Cutting Edge: Silencing Suppressor of Cytokine Signaling 3 Expression in Dendritic Cells Turns CD28-Ig from Immune Adjuvant to Suppressant

• Published in: The Journal of immunology (1950) 2005-06, Vol.174 (11), p.6582-6586
• Main Authors: Orabona, Ciriana, Belladonna, Maria Laura, Vacca, Carmine, Bianchi, Roberta, Fallarino, Francesca, Volpi, Claudia, Gizzi, Stefania, Fioretti, Maria Cristina, Grohmann, Ursula, Puccetti, Paolo
• Format: Article
• Language: English
• Subjects: Abatacept; Adjuvants, Immunologic - physiology; Animals; Antigen Presentation - immunology; CD28 Antigens - pharmacology; CD8 Antigens - biosynthesis; Dendritic Cells - enzymology; Dendritic Cells - immunology; Dendritic Cells - metabolism; DNA-Binding Proteins - metabolism; Female; Gene Silencing - immunology; Immunoconjugates - pharmacology; Immunosuppressive Agents - pharmacology; Indoleamine-Pyrrole 2,3,-Dioxygenase; Interferon-gamma - physiology; Interleukin-6 - pharmacology; Mice; Mice, Inbred DBA; Phosphorylation; Recombinant Fusion Proteins - physiology; Repressor Proteins - antagonists & inhibitors; Repressor Proteins - biosynthesis; Repressor Proteins - genetics; RNA, Small Interfering - pharmacology; STAT3 Transcription Factor; Suppressor of Cytokine Signaling 3 Protein; Suppressor of Cytokine Signaling Proteins; Trans-Activators - metabolism; Transcription Factors - antagonists & inhibitors; Transcription Factors - biosynthesis; Transcription Factors - deficiency; Transcription Factors - genetics; Tryptophan - metabolism; Tryptophan Oxygenase - biosynthesis
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.174.11.6582

CTLA-4-Ig and CD28-Ig are both agonist ligands of B7 coreceptor molecules on mouse dendritic cells (DCs), yet they bias the downstream response in opposite directions, and CTLA-4-Ig promotes tolerance, whereas CD28-Ig favors the onset of immunity. Although B7 engagement by either ligand leads to a mixed cytokine response, a dominant IL-6 production in response to CD28-Ig prevents the IFN-gamma-driven induction of immunosuppressive tryptophan catabolism mediated by IDO. In the present study, we show that silencing the expression of suppressor of cytokine signaling 3 (SOCS3) in DCs by RNA interference renders CD28-Ig capable of activating IDO, likely as a result of unrestrained IFN-gamma signaling and IFN-gamma-like actions of IL-6. Thus, in the absence of SOCS3, CD28-Ig becomes immunosuppressive and mimics the action of CTLA-4-Ig on tryptophan catabolism.