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ThPOK acts late in specification of the helper T cell lineage and suppresses Runx-mediated commitment to the cytotoxic T cell lineage

Nature Immunology volume 9, pages 1131–1139 (2008)Cite this article

Abstract

The transcription factor ThPOK is required and sufficient for the generation of CD4+CD8− thymocytes, yet the mechanism by which ThPOK orchestrates differentiation into the CD4+ helper T cell lineage remains unclear. Here we used reporter mice to track the expression of transcription factors in developing thymocytes. Distal promoter–driven expression of the gene encoding the transcription factor Runx3 was restricted to major histocompatibility complex (MHC) class I–selected thymocytes. In ThPOK-deficient mice, such expression was derepressed in MHC class II–selected thymocytes, which contributed to their redirection to the CD8+ T cell lineage. In the absence of both ThPOK and Runx, redirection was prevented and cells potentially belonging to the CD4+ lineage, presumably specified independently of ThPOK, were generated. Our results suggest that MHC class II–selected thymocytes are directed toward the CD4+ lineage independently of ThPOK but require ThPOK to prevent Runx-dependent differentiation toward the CD8+ lineage.

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Figure 1: CD8 SP lineage–specific Runx3 expression from its distal promoter is required for Cd4 silencing and CD103 expression in CD8+ T cells.
Figure 2: Runx3d and ThPOK reporter expression in developing thymocytes.
Figure 3: CD8+ lineage–specific Runx3dYFP expression is derepressed in ThPOK-deficient MHC class II-restricted thymocytes.
Figure 4: CD4+ T cell differentiation in the presence of lower quantities of ThPOK.
Figure 5: ThPOK is dispensable for the differentiation of CD4 SP thymocytes.
Figure 6: Derepression of CD8+ lineage-specific genes in MHC class II–restricted cells in the absence of ThPOK or in the presence of an insufficient amount of ThPOK.

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Acknowledgements

We thank the Rockefeller University Gene Targeting Facility for the generation of ThPOK mutant mice with B6-C2J embryonic stem cells; J.H. Dong, A. Auerbach and W. Ho for microinjection; members of the laboratory for discussion; and J. Huh, M. Chong, A. Collins and S. Schwab for critical reading of the manuscript. Supported by the Leukemia and Lymphoma Society (T.E.) and the Howard Hughes Medical Institute (D.R.L.).

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  1. Molecular Pathogenesis Program, The Helen and Martin Kimmel Center for Biology and Medicine at the Skirball Institute of Biomolecular Medicine, New York University School of Medicine, New York, 10016, New York, USA

    Takeshi Egawa & Dan R Littman

  2. The Howard Hughes Medical Institute, The Helen and Martin Kimmel Center for Biology and Medicine at the Skirball Institute of Biomolecular Medicine, New York University School of Medicine, New York, 10016, New York, USA

    Dan R Littman

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  1. Takeshi Egawa
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T.E. did all the experiments; and T.E. and D.R.L. designed the experiments and wrote the manuscript.

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Correspondence to Takeshi Egawa or Dan R Littman.

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Egawa, T., Littman, D. ThPOK acts late in specification of the helper T cell lineage and suppresses Runx-mediated commitment to the cytotoxic T cell lineage. Nat Immunol 9, 1131–1139 (2008). https://doi.org/10.1038/ni.1652

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