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FoxP3 interacts with linker histone H1.5 to modulate gene expression and program Treg cell activity

Genes & Immunity volume 12, pages 559–567 (2011)Cite this article

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Abstract

The forkhead box transcription factor FoxP3 controls the development and function of CD4+CD25+ regulatory T (Treg) cell. FoxP3 modulates gene expression in Treg cells by multiple epigenetic mechanisms that are not clearly defined. We identified FoxP3-interacting proteins in human T cells by co-immunoprecipitation/MS. We discovered that FoxP3 interacted with linker histone H1.5 via the leucine zipper (LZ) domain. Two independent IPEX patient-derived single residue mutations in the LZ of FoxP3 both abrogated its interaction with H1.5. Functionally, FoxP3 and H1.5 cooperatively repressed interleukin-2 (IL-2) expression in human T cells; and silencing of H1.5 expression inhibited the ability of FoxP3 to suppress IL-2 expression. We show that FoxP3 specifically enhanced H1.5 association at the IL-2 promoter, but reduce its association at the CTLA4 promoter, correlated with higher or lower histone acetylation of the respective promoters. Finally, silencing of H1.5 expression in human Treg cells impaired the Treg function to suppress target T cells. We conclude that FoxP3 interacts with H1.5 to alter its binding to target genes to modulate their expression and to program Treg function.

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Acknowledgements

We thank Drs Yi Zhang, Art Skoultchi, Jenny Ting, Yue Xiong and members of the Su lab for critical reading and/or discussion of the manuscript. The project was supported by grants from NIH (AI048407 & AI077454 to LS, AI065303 to DU) and UNC training grant (106693-39-RFMT to SMC).

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Authors and Affiliations

  1. Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, USA

    S L Mackey-Cushman, J Gao, J-i Nunoya & L Su

  2. Department of Microbiology and Immunology, University of North Carolina, Chapel Hill, NC, USA

    D A Holmes & L Su

  3. Department of Microbiology, New York University School of Medicine, New York, NY, USA

    R Wang & D Unutmaz

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  1. S L Mackey-Cushman
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  2. J Gao
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Correspondence to L Su.

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Mackey-Cushman, S., Gao, J., Holmes, D. et al. FoxP3 interacts with linker histone H1.5 to modulate gene expression and program Treg cell activity. Genes Immun 12, 559–567 (2011). https://doi.org/10.1038/gene.2011.31

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