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Hlx is induced by and genetically interacts with T-bet to promote heritable TH1 gene induction

Nature Immunology volume 3, pages 652–658 (2002)Cite this article

Abstract

Type 1 helper T (TH1) cells are essential for cellular immunity, but their ontogeny, maturation and durability remain poorly understood. By constructing a dominant-negative form of T-bet, we were able to determine the role played by this lineage-inducing trans-activator in the establishment and maintenance of heritable TH1 gene expression. Optimal induction of interferon-γ (IFN-γ) expression required genetic interaction between T-bet and its target, the homeoprotein Hlx. In fully mature TH1 cells, reiteration of IFN-γ expression and stable chromatin remodeling became relatively independent of T-bet activity and coincided with demethylation of DNA. In contrast, some lineage attributes, such as expression of IL-12Rβ2 (interleukin 12 receptor β2), required ongoing T-bet activity in mature TH1 cells and their progeny. These findings suggest that heritable states of gene expression might be maintained by continued expression of the inducing factor or by a mechanism that confers a stable imprint of the induced state.

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Figure 1: Effects of DN T-bet on IFN-γ expression during TH1 differentiation.
Figure 2: Effects of DN T-bet on the TH1 identity.
Figure 3: The role of T-bet in chromatin remodeling and its maintenance at the Ifng locus.
Figure 4: Hlx encodes a TH1-specific transcription factor.
Figure 5: Hlx is a genetic target of T-bet.
Figure 6: Hlx genetically interacts with T-bet to induce heritable TH1 gene expression.
Figure 7: Progressive demethylation of Ifng during TH1 maturation.

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Acknowledgements

We thank M. Weiss for helpful discussion; W. Pear and B. Cobb for advice on retrovirus production; V. Amorosa, J. Hartman, E. L. Pearce, M. Kessler and A. Villarino for assistance; D. Kessler for the cDNA of Drosophila engrailed repression domain; and W. DeMuth for cell sorting. Supported by the NIH (AI42370 to SLR).

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Authors and Affiliations

  1. Abramson Family Cancer Research Institute and Department of Medicine, University of Pennsylvania, Philadelphia, 19104-6160, PA, USA

    Alan C. Mullen, Anne S. Hutchins, Frances A. High, Hubert W. Lee, Kara J. Sykes, Lewis A. Chodosh & Steven L. Reiner

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  1. Alan C. Mullen
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Correspondence to Steven L. Reiner.

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Mullen, A., Hutchins, A., High, F. et al. Hlx is induced by and genetically interacts with T-bet to promote heritable TH1 gene induction. Nat Immunol 3, 652–658 (2002). https://doi.org/10.1038/ni807

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