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Distinct functions for the transcription factors GATA-3 and ThPOK during intrathymic differentiation of CD4+ T cells

Nature Immunology volume 9, pages 1122–1130 (2008)Cite this article

Abstract

The transcription factors GATA-3 and ThPOK are required for intrathymic differentiation of CD4+ T cells, but their precise functions in this process remain unclear. Here we show that, contrary to previous findings, Gata3 disruption blocked differentiation into the CD4+ T cell lineage before commitment to the CD4+ lineage and in some contexts permitted the 'redirection' of major histocompatibility complex class II–restricted thymocytes into the CD8+ lineage. GATA-3 promoted ThPOK expression and bound to a region of the locus encoding ThPOK established as being critical for ThPOK expression. Finally, ThPOK promoted differentiation into the CD4+ lineage in a way dependent on GATA-3 but inhibited differentiation into the CD8+ lineage independently of GATA-3. We propose that GATA-3 acts as a specification factor for the CD4+ lineage 'upstream' of the ThPOK-controlled CD4+ commitment checkpoint.

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Figure 1: ThPOK disruption does not affect CD4+ differentiation before the CD4+-CD8+ lineage-commitment checkpoint.
Figure 2: Gata3 disruption prevents CD4+ differentiation but not positive selection.
Figure 3: GATA-3-deficient MHC class II–restricted thymocytes undergo intrathymic signaling and are inefficiently redirected into the CD8+ lineage.
Figure 4: GATA-3 is required 'upstream' of ThPOK.
Figure 5: ThPOK needs GATA-3 to promote CD4+ but not to inhibit CD8+ differentiation.
Figure 6: GATA-3 is recruited to a region of the ThPOK locus critical for ThPOK expression.

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Acknowledgements

We thank Y. Xiong, R. Jenkinson and J. Rozenberg for assistance with ChIP assays; E. Southon for embryonic stem cell recombination; M. Pellegrini and A. Nussenzweig for assistance with recombination-mediated genetic engineering; E. Castro and G. Sanchez for mouse technical assistance; B. Taylor and S. Banerjee for cell sorting; and A. Gégonne and A. Singer for reading the manuscript. Supported by the Intramural Research Programs of the National Cancer Institute, Center for Cancer Research, and of the National Institute of Allergy and Infectious Diseases, National Institutes of Health.

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Authors and Affiliations

  1. Laboratory of Immune Cell Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, 20892, Maryland, USA

    Lie Wang, Kathryn F Wildt & Rémy Bosselut

  2. Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, 20892, Maryland, USA

    Jinfang Zhu & William E Paul

  3. Laboratory of Cellular and Molecular Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, 20892, Maryland, USA

    Xianyu Zhang & B J Fowlkes

  4. National Cancer Institute–Science Applications International Corporation, Frederick, 21702, Maryland, USA

    Lionel Feigenbaum

  5. Mouse Cancer Genetics Program, Center for Cancer Research, National Cancer Institute, Frederick, 21702, Maryland, USA

    Lino Tessarollo

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Wang, L., Wildt, K., Zhu, J. et al. Distinct functions for the transcription factors GATA-3 and ThPOK during intrathymic differentiation of CD4+ T cells. Nat Immunol 9, 1122–1130 (2008). https://doi.org/10.1038/ni.1647

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