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Epigenetic and Transcriptional Programs Lead to Default IFN- Production by T Cells¹

Liang Chen^2,3,*, Weifeng He^2,4,*, Sean T. Kim^2,, Jian Tao^*, Yunfei Gao^5,*, Hongbo Chi, Andrew M. Intlekofer, Bohdan Harvey^*, Steven L. Reiner, Zhinan Yin^6,*, Richard A. Flavell and Joe Craft^*,

^* Section of Rheumatology, Department of Medicine and Section of Immunobiology, Yale School of Medicine, New Haven, Connecticut, 06520; and University of Pennsylvania School of Medicine, Philadelphia, PA 19104

T cells have unique features and functions compared with T cells and have been proposed to bridge the innate and adaptive immune responses. Our earlier studies demonstrated that splenic T cells predominantly produce IFN- upon activation in vitro, which is partially due to the expression of the Th1-specific transcription factor T-bet. In this study we have explored the epigenetic and transcriptional programs that underlie default IFN- production by T cells. We show that the kinetics of IFN- transcription is faster in T cells compared with CD4⁺ and CD8⁺ T cells and that T cells produce significantly greater amounts of IFN- in a proliferation-independent manner when compared with other T cell subsets. By analyzing the methylation pattern of intron 1 of the ifn- locus, we demonstrate that this region in naive T cells is hypomethylated relative to the same element in naive CD4⁺ and CD8⁺ T cells. Furthermore, naive T cells constitutively express eomesodermin (Eomes), a transcription factor important for IFN- production in CD8⁺ T cells, and Eomes expression levels are enhanced upon activation. Retroviral transduction of activated T cells from both wild-type and T-bet-deficient mice with a dominant negative form of Eomes significantly reduced IFN- production, indicating a critical role for this transcription factor in mediating IFN- production by T cells in a T-bet-independent manner. Our results demonstrate that both epigenetic and transcriptional programs contribute to the early vigorous IFN- production by T cells.

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 an Arthritis Foundation Investigator Award, National Institute of Arthritis and Musculoskeletal and Skin Diseases Grant K01 AR 02188, National Institutes of Health Grants R01AI56219 (to Z.Y.), AR40072, and 44076, and support from the Arthritis Foundation (to J.C.).

² L.C. and W.H. contributed equally to this work.

³ Current address: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston MA 02115.

⁴ Current address: State Key Laboratory of Trauma, Burns, and Combined Injury, Southwest Hospital, Third Military Medical University, Chongqing 40038, Peoples Republic of China.

⁵ Current address: Department of Immunology, University of Toronto, Canada.

⁶ Address correspondence and reprint requests to Dr. Zhinan Yin, Section of Rheumatology, Yale School of Medicine, Box 208031, The Anlyan Center, Room 517, 300 Cedar Street, New Haven, CT 06520. E-mail address: zhinan.yin{at}yale.edu

⁷ Abbreviations used in this paper: Eomes, eomesodermin; DN, dominant negative; HPRT, hypoxanthine phosphoribosyltransferase; Q-PCR, quantitative PCR.