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A ThPOK-LRF transcriptional node maintains the integrity and effector potential of post-thymic CD4+ T cells

Nature Immunology volume 15, pages 947956 (2014) | Download Citation

Abstract

The transcription factor ThPOK promotes CD4+ T cell differentiation in the thymus. Here, using a mouse strain that allows post-thymic gene deletion, we show that ThPOK maintains CD4+ T lineage integrity and couples effector differentiation to environmental cues after antigenic stimulation. ThPOK preserved the integrity and amplitude of effector responses and was required for proper differentiation of types 1 and 2 helper T cells in vivo by restraining the expression and function of Runx3, a nuclear factor crucial for cytotoxic T cell differentiation. The transcription factor LRF acts redundantly with ThPOK to prevent the transdifferentiation of mature CD4+ T cells into CD8+ T cells. As such, the ThPOK-LRF transcriptional module was essential for CD4+ T cell integrity and responses.

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Acknowledgements

We thank T. Ciucci for experimental assistance and discussions; T.-A. Lewis for animal care and genotyping; M. McGinty and Q. Xiao for technical assistance; X. Wu for microarray analyses; D. Littman, P.P. Pandolfi and S. Reiner for mice; M. Grigg for the T. gondii strain; J. Grainger, T. Hand and S. Spencer for discussions; and J. Ashwell and J. Brenchley for reading the manuscript. Supported by the US National Institutes of Health Intramural Research Programs of the National Cancer Institute, Center for Cancer Research, the National Institute of Allergy and Infectious Diseases and the Eunice Kennedy Shriver National Institute of Child Health and Human Development.

Author information

Author notes

    • Lie Wang
    • , Elizabeth Wohlfert
    •  & Ki-Duk Song

    Present addresses: Institute of Immunology, Zhejiang University School of Medicine, Hangzhou, China (L.W.), Department of Microbiology and Immunology, University at Buffalo School of Medicine and Biomedical Sciences, Buffalo, New York, USA (E.W.), Center for Agricultural Biomaterials, Seoul National University, Seoul, South Korea (K.-D. S.).

Affiliations

  1. Laboratory of Immune Cell Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.

    • Melanie S Vacchio
    • , Lie Wang
    • , Andrea C Carpenter
    • , Yumei Xiong
    • , Linus C Williams
    •  & Rémy Bosselut
  2. Mucosal Immunology Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.

    • Nicolas Bouladoux
    • , Elizabeth Wohlfert
    •  & Yasmine Belkaid
  3. Section on Cellular and Developmental Biology, Program in Genomics of Differentiation, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, USA.

    • Ki-Duk Song
    •  & Paul E Love

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Contributions

M.S.V., L.W., Y.B. and R.B. designed the research; M.S.V., L.W., N.B, A.C.C., Y.X., L.C.W. and E.W. performed and analyzed experiments; K.-D.S. and P.E.L. constructed and provided CD2-Cre mice; R.B. supervised the research; M.S.V. and R.B. wrote the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Rémy Bosselut.

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https://doi.org/10.1038/ni.2960

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