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The transcription factor ThPOK suppresses Runx3 and imposes CD4+ lineage fate by inducing the SOCS suppressors of cytokine signaling

Nature Immunology volume 15, pages 638645 (2014) | Download Citation

Abstract

Lineage fate in the thymus is determined by mutually exclusive expression of the transcription factors ThPOK and Runx3, with ThPOK imposing the CD4+ lineage fate and Runx3 promoting the CD8+ lineage fate. While it is known that cytokine signals induce thymocytes to express Runx3, it is not known how ThPOK prevents thymocytes from expressing Runx3 and adopting the CD8+ lineage fate, nor is it understood why ThPOK itself imposes the CD4+ lineage fate on thymocytes. We now report that genes encoding members of the SOCS (suppressor of cytokine signaling) family are critical targets of ThPOK and that their induction by ThPOK represses Runx3 expression and promotes the CD4+ lineage fate. Thus, induction of SOCS-encoding genes is the main mechanism by which ThPOK imposes the CD4+ lineage fate in the thymus.

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Acknowledgements

We thank D. Singer and R. Hodes for critical review of this manuscript; R. Bosselut (National Cancer Institute) for Thpok−/− and ThPOK-Tg (C8) mice; J. Ihle (St. Jude Children's Research Hospital) for mice with germline deficiency in Socs1 and Ifng; D. Kappes (Fox Chase Cancer Center) for Thpokhd/hd mice; T. Kay (St. Vincent's Institute of Medical Research) for human CD4–Socs1 reporter mice; and M. Kubo (RIKEN) for SOCS1-Tg mice. Supported by the Intramural Research Program of the US National Institutes of Health, National Cancer Institute, Center for Cancer Research.

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Affiliations

  1. Experimental Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.

    • Megan A Luckey
    • , Motoko Y Kimura
    • , Adam T Waickman
    • , Alfred Singer
    •  & Jung-Hyun Park
  2. Leidos Biomedical Research, Frederick National Laboratory for Cancer Research, Frederick, Maryland, USA.

    • Lionel Feigenbaum

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Contributions

M.A.L., M.Y.K. and A.T.W. designed and did experiments, and analyzed data; L.F. generated reagents; A.S. designed the study, analyzed data and wrote the manuscript; and J.-H.P. designed and did experiments, analyzed data, provided overall direction and wrote the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Jung-Hyun Park.

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https://doi.org/10.1038/ni.2917

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