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The zinc finger transcription factor Th-POK regulates CD4 versus CD8 T-cell lineage commitment

Nature volume 433, pages 826–833 (2005)Cite this article

Abstract

Development of immature T-cell precursors (thymocytes) to either the CD4 helper or CD8 killer T-cell lineages correlates precisely with their T-cell receptor specificity for major histocompatibility complex class II or class I molecules, respectively, indicating that the process is carefully regulated. Although intensively studied owing to its importance in determining the composition of the mature T-cell compartment and as a general model of binary lineage decisions, the underlying molecular pathways remain obscure. We have previously reported a spontaneous mouse mutant (HD (helper deficient) mice) in which lineage commitment is specifically perturbed without affecting positive selection. Here we show that a point mutation in the zinc finger transcription factor Th-POK (T-helper-inducing POZ/Krüppel-like factor) is responsible for redirection of class-II-restricted thymocytes to the CD8 lineage in HD mice. Furthermore, we demonstrate that constitutive expression of this factor during thymic development leads to redirection of class-I-restricted thymocytes to the CD4 lineage, indicating that Th-POK is a master regulator of lineage commitment.

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Figure 1: Constitutive CD4 expression or ablation of CD8 does not correct the HD phenotype.
Figure 2: Genetic mapping of the HD defect.
Figure 3: BAC complementation of the HD phenotype.
Figure 4: The HD mutation is located in the second zinc finger domain of Th-POK.
Figure 5: Lineage- and stage-specific expression of Th-POK during thymic development.
Figure 6: Ectopic expression of Th-POK causes redirection of class-I-restricted thymocytes to the CD4 lineage.

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Acknowledgements

We acknowledge technical assistance with flow cytometry by J. Oesterling, and animal husbandry by members of the Laboratory Animal Facility. V.P.D. was responsible for initial genetic mapping of the HD mutation to a resolution of 4 cM. We thank D. Wiest for comments on the manuscript. This work was supported by National Institutes of Health Grants to D.J.K, an NIH Core Grant, and also an appropriation from the Commonwealth of Pennsylvania.

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Author notes

  1. Vibhuti P. Dave

    Present address: Lymphocyte Development Laboratory, Room 1045, I.R.C.M., 110 Pine Avenue West, Montreal, Quebec, H2W 1R7, Canada

  2. Xiao He and Xi He: These authors contributed equally to this work

Authors and Affiliations

  1. Fox Chase Cancer Center, 7701 Burholme Avenue, Philadelphia, Pennsylvania, 19111, USA

    Xiao He, Xi He, Vibhuti P. Dave, Yi Zhang, Xiang Hua, Emmanuelle Nicolas & Dietmar J. Kappes

  2. Department of Chemistry And Biochemistry, University of Oklahoma, 620 Parrington Oval, Room 208, Norman, Oklahoma, 73019, USA

    Weihong Xu & Bruce A. Roe

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Correspondence to Dietmar J. Kappes.

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Supplementary information

Supplementary Figures 1-3

This file contains Supplementary Figures 1 (FACS analysis of thymocytes from male and female HY+ HD / and HD+/+ mice), 2 (FACS analysis of thymocytes and PBLs from BAC transgenic HD-/- mice demonstrating restoration of CD4 development) and 3 (northern blot analysis of Th-POK mRNA expression in various mouse tissues). (PDF 871 kb)

Supplementary Table 1

Results of BAC transgenic complementation analysis. (PDF 523 kb)

Supplementary Data

This file contains Supplementary Methods (details of genetic mapping and BAC complementation analysis), Supplementary Figure legends and Supplementary Table legend. (DOC 10 kb)

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He, X., He, X., Dave, V. et al. The zinc finger transcription factor Th-POK regulates CD4 versus CD8 T-cell lineage commitment. Nature 433, 826–833 (2005). https://doi.org/10.1038/nature03338

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