Cutting edge: silencing suppressor of cytokine signaling 3 expression in dendritic cells turns CD28-Ig from immune adjuvant to suppressant.
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.
Orabona
Ciriana
C
Department of Experimental Medicine, University of Perugia, Italy.
Belladonna
Maria Laura
ML
Vacca
Carmine
C
Bianchi
Roberta
R
Fallarino
Francesca
F
Volpi
Claudia
C
Gizzi
Stefania
S
Fioretti
Maria Cristina
MC
Grohmann
Ursula
U
Puccetti
Paolo
P
D000069594:Abatacept; D000276:Adjuvants, Immunologic / Q000502:physiology*; D000818:Animals; D017951:Antigen Presentation / Q000276:immunology; D018106:CD28 Antigens / Q000494:pharmacology*; D016827:CD8 Antigens / Q000096:biosynthesis; D004268:DNA-Binding Proteins / Q000378:metabolism; D003713:Dendritic Cells / Q000201:enzymology / Q000276:immunology* / Q000378:metabolism*; D005260:Female; D020868:Gene Silencing / Q000276:immunology; D018796:Immunoconjugates / Q000494:pharmacology; D007166:Immunosuppressive Agents / Q000494:pharmacology; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D007371:Interferon-gamma / Q000502:physiology; D015850:Interleukin-6 / Q000494:pharmacology; D051379:Mice; D008811:Mice, Inbred DBA; D010766:Phosphorylation; D034741:RNA, Small Interfering / Q000494:pharmacology; D011993:Recombinant Fusion Proteins / Q000502:physiology; D012097:Repressor Proteins / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics*; D050796:STAT3 Transcription Factor; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D015534:Trans-Activators / Q000378:metabolism; D014157:Transcription Factors / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics*; D014364:Tryptophan / Q000378:metabolism; D014366:Tryptophan Oxygenase / Q000096:biosynthesis
D000276:Adjuvants, Immunologic; D018106:CD28 Antigens; D016827:CD8 Antigens; D004268:DNA-Binding Proteins; D018796:Immunoconjugates; D007166:Immunosuppressive Agents; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D015850:Interleukin-6; D034741:RNA, Small Interfering; D011993:Recombinant Fusion Proteins; D012097:Repressor Proteins; D050796:STAT3 Transcription Factor; C491411:Socs3 protein, mouse; C494087:Stat3 protein, mouse; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D015534:Trans-Activators; D014157:Transcription Factors; D000069594:Abatacept; D007371:Interferon-gamma; D014364:Tryptophan; D014366:Tryptophan Oxygenase