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Epigenetic and Transcriptional Programs Lead to Default IFN-γ Production by γδ T Cells

Liang Chen, Weifeng He, Sean T. Kim, Jian Tao, Yunfei Gao, Hongbo Chi, Andrew M. Intlekofer, Bohdan Harvey, Steven L. Reiner, Zhinan Yin, Richard A. Flavell and Joe Craft
J Immunol March 1, 2007, 178 (5) 2730-2736; DOI: https://doi.org/10.4049/jimmunol.178.5.2730
Liang Chen
*Section of Rheumatology, Department of Medicine and
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Weifeng He
*Section of Rheumatology, Department of Medicine and
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Sean T. Kim
†Section of Immunobiology, Yale School of Medicine, New Haven, Connecticut, 06520; and
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Jian Tao
*Section of Rheumatology, Department of Medicine and
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Yunfei Gao
*Section of Rheumatology, Department of Medicine and
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Hongbo Chi
†Section of Immunobiology, Yale School of Medicine, New Haven, Connecticut, 06520; and
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Andrew M. Intlekofer
‡University of Pennsylvania School of Medicine, Philadelphia, PA 19104
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Bohdan Harvey
*Section of Rheumatology, Department of Medicine and
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Steven L. Reiner
‡University of Pennsylvania School of Medicine, Philadelphia, PA 19104
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Zhinan Yin
*Section of Rheumatology, Department of Medicine and
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Richard A. Flavell
†Section of Immunobiology, Yale School of Medicine, New Haven, Connecticut, 06520; and
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Joe Craft
*Section of Rheumatology, Department of Medicine and
†Section of Immunobiology, Yale School of Medicine, New Haven, Connecticut, 06520; and
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Abstract

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

  • Received April 11, 2006.
  • Accepted December 7, 2006.
  • Copyright © 2007 by The American Association of Immunologists
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The Journal of Immunology: 178 (5)
The Journal of Immunology
Vol. 178, Issue 5
1 Mar 2007
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Epigenetic and Transcriptional Programs Lead to Default IFN-γ Production by γδ T Cells
Liang Chen, Weifeng He, Sean T. Kim, Jian Tao, Yunfei Gao, Hongbo Chi, Andrew M. Intlekofer, Bohdan Harvey, Steven L. Reiner, Zhinan Yin, Richard A. Flavell, Joe Craft
The Journal of Immunology March 1, 2007, 178 (5) 2730-2736; DOI: 10.4049/jimmunol.178.5.2730

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Epigenetic and Transcriptional Programs Lead to Default IFN-γ Production by γδ T Cells
Liang Chen, Weifeng He, Sean T. Kim, Jian Tao, Yunfei Gao, Hongbo Chi, Andrew M. Intlekofer, Bohdan Harvey, Steven L. Reiner, Zhinan Yin, Richard A. Flavell, Joe Craft
The Journal of Immunology March 1, 2007, 178 (5) 2730-2736; DOI: 10.4049/jimmunol.178.5.2730
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