The Journal of Experimental Medicine
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Published 18 October 2004. doi:10.1084/jem.20040942
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 200, Number 8, 1051-1062
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CTLA-4–Ig Activates Forkhead Transcription Factors and Protects Dendritic Cells from Oxidative Stress in Nonobese Diabetic Mice

Francesca Fallarino1, Roberta Bianchi1, Ciriana Orabona1, Carmine Vacca1, Maria L. Belladonna1, Maria C. Fioretti1, David V. Serreze2, Ursula Grohmann1, and Paolo Puccetti1

1 Department of Experimental Medicine, University of Perugia, Perugia 06126, Italy
2 The Jackson Laboratory, Bar Harbor, ME 04609

Address correspondence to Ursula Grohmann, Dept. of Experimental Medicine, Section of Pharmacology, University of Perugia, Via del Giochetto, Perugia 06126, Italy. Phone: 39-075-585-7460; Fax: 39-075-585-7473; email: ugrohmann{at}tin.it

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.

Key Words: NOD mice • dendritic cells • CTLA-4 • superoxide dismutase • signal transduction

U. Grohmann and P. Puccetti are senior authors on this paper.

Abbreviations used in this paper: 1-MT, 1-methyl-DL-tryptophan; 2-MeOE2, 2-methoxyestradiol; CTLA-4, cytotoxic T lymphocyte antigen 4; FOXO, Forkhead Box class O; GED, guanidinoethyl disulphide; IDO, indoleamine 2,3-dioxygenase; MnTBAP, Mn(III)tetrakis(4-benzoic acid)porphyrin chloride; NO, nitric oxide; NOD, nonobese diabetic; PI3K, phosphatidylinositol 3 kinase; RLU, relative light unit; siRNA, small interfering RNA; SOD, superoxide dismutase.


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