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IFN--Dependent Regulatory Circuits in Immune Inflammation Highlighted in Diabetes¹

Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110

We demonstrate diverse roles of IFN- in the induction and regulation of immune-mediated inflammation using a transfer model of autoimmune diabetes. The diabetogenic CD4⁺BDC2.5 (BDC) T cell clone upon transfer into NOD.scid mice induced destruction of islets of Langerhans leading to diabetes. Administration of a neutralizing Ab to IFN- (H22) resulted in long-term protection (LTP) from diabetes, with inflammation but persistence of a significant, albeit decreased, number of β cells. BDC T cells were a mixture of cells expressing high, intermediate, and low levels of the TCR. Clonotype^low BDC T cells were required for LTP. Furthermore, islet-infiltrating leukocytes in the LTP mice contained Foxp3⁺CD4 T cells. Islet inflammation in both diabetic and LTP mice was characterized by heavy infiltration of macrophages. Gene expression profiles indicated that macrophages in diabetic mice were M1 type, while LTP mice contained M2 differentiated. The LTP was abolished if mice were treated with either Ab-depleting CD4 T cells or a neutralizing Ab to CTLA-4, in this case, only at a late stage. Neutralization of IL-10, TGF-β, glucocorticoid-induced TNF receptor (GITR), or CD25 had no effect. Transfer of only clonotype^high- expressing BDC T cells induced diabetes; in contrast, H22 Abs did not inhibit diabetes. While clonotype^high T cells induced diabetes even when IFN- was neutralized, paradoxically there was reduced inflammation and no diabetes if host myeloid cells lacked IFN- receptor. Hence, using monoclonal CD4 T cells, IFN- can have a wide diversity of roles, depending on the setting of the immune process.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by National Institutes of Health Grants DK058177 (to E.R.U.) and K08 DK066062 and DRTC (Diabetes Research and Training Center) 5 P60 DK20579 (to J.C.M.), the Juvenile Diabetic Research Foundation, the Kilo Diabetes and Vascular Research Foundation, and the Multiplex Gene Analysis Core of the Siteman Cancer Center (supported in part by National Cancer Institute Grant P30 CA91842).

² Address correspondence and reprint requests to Dr. Emil R. Unanue, Department of Pathology and Immunology, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, MO 63110. E-mail address: unanue{at}pathbox.wustl.edu

³ Abbreviations used in this paper: BDC, BDC2.5; BDC.scid, BDC2.5/NOD.scid; GITR, glucocorticoid-induced TNF receptor; GO, gene ontology; IFN-R^–/–, IFN- receptor^–/–; LTP, long-term protected; NOD.Rag, NOD.Rag-1^–/–; NOD.scid, NOD.CB17-Prkdc^scid/J.

⁴ The online version of this article contains supplemental material.