CTLA-4-Ig activates forkhead transcription factors and protects dendritic cells from oxidative stress in nonobese diabetic mice.
Prediabetes and diabetes in nonobese diabetic (NOD) mice have been targeted by a variety of immunotherapies, including the use of a soluble form of cytotoxic T lymphocyte antigen 4 (CTLA-4) and interferon (IFN)-gamma. The cytokine, however, fails to activate tolerogenic properties in dendritic cells (DCs) from highly susceptible female mice early in prediabetes. The defect is characterized by impaired induction of immunosuppressive tryptophan catabolism, is related to transient blockade of the signal transducer and activator of transcription (STAT)1 pathway of intracellular signaling by IFN-gamma, and is caused by peroxynitrite production. Here, we show that soluble CTLA-4 imparts suppressive properties to DCs from early prediabetic NOD female mice through mechanisms that rely on autocrine signaling by IFN-gamma. Although phosphorylation of STAT1 in response to IFN-gamma is compromised in those mice, CTLA-4 obviates the defect. IFN-gamma-driven expression of tryptophan catabolism by CTLA-4-immunoglobulin is made possible through the concomitant activation of the Forkhead Box class O (FOXO) transcription factor FOXO3a, induction of the superoxide dismutase gene, and prevention of peroxynitrite formation.
Fallarino
Francesca
F
Department of Experimental Medicine, University of Perugia, Perugia 06126, Italy.
Bianchi
Roberta
R
Orabona
Ciriana
C
Vacca
Carmine
C
Belladonna
Maria L
ML
Fioretti
Maria C
MC
Serreze
David V
DV
Grohmann
Ursula
U
Puccetti
Paolo
P
D000069594:Abatacept; D000818:Animals; D002867:Chromones / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000378:metabolism; D003713:Dendritic Cells / Q000378:metabolism*; D005260:Female; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; D018796:Immunoconjugates / Q000494:pharmacology*; D007371:Interferon-gamma / Q000494:pharmacology; D008297:Male; D008665:Metalloporphyrins / Q000494:pharmacology; D051379:Mice; D016688:Mice, Inbred NOD; D009025:Morpholines / Q000494:pharmacology; D018384:Oxidative Stress; D051059:PTEN Phosphohydrolase; D030421:Peroxynitrous Acid / Q000096:biosynthesis; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D010766:Phosphorylation; D017027:Protein Tyrosine Phosphatases / Q000235:genetics; D050794:STAT1 Transcription Factor; D015398:Signal Transduction; D015534:Trans-Activators / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000235:genetics
D002867:Chromones; D004268:DNA-Binding Proteins; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; C474033:FoxO3 protein, mouse; D018796:Immunoconjugates; D008665:Metalloporphyrins; D009025:Morpholines; D050794:STAT1 Transcription Factor; C494080:Stat1 protein, mouse; D015534:Trans-Activators; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; C097284:manganese(III)-tetrakis(4-benzoic acid)porphyrin; D030421:Peroxynitrous Acid; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D000069594:Abatacept; D007371:Interferon-gamma; D019869:Phosphatidylinositol 3-Kinases; D017027:Protein Tyrosine Phosphatases; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse