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Elevated and sustained expression of the transcription factors Egr1 and Egr2 controls NKT lineage differentiation in response to TCR signaling

Nature Immunology volume 13, pages 264–271 (2012)Cite this article

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A Corrigendum to this article was published on 19 March 2013

This article has been updated

Abstract

Interactions driven by the T cell antigen receptor (TCR) determine the lineage fate of CD4+CD8+ thymocytes, but the molecular mechanisms that induce the lineage-determining transcription factors are unknown. Here we found that TCR-induced transcription factors Egr2 and Egr1 had higher and more-prolonged expression in precursors of the natural killer T (NKT) than in cells of conventional lineages. Chromatin immunoprecipitation followed by deep sequencing showed that Egr2 directly bound and activated the promoter of Zbtb16, which encodes the NKT lineage–specific transcription factor PLZF. Egr2 also bound the promoter of Il2rb, which encodes the interleukin 2 (IL-2) receptor β-chain, and controlled the responsiveness to IL-15, which signals the terminal differentiation of the NKT lineage. Thus, we propose that persistent higher expression of Egr2 specifies the early and late stages of NKT lineage differentiation, providing a discriminating mechanism that enables TCR signaling to 'instruct' a thymic lineage.

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Figure 1: Higher and more-prolonged expression of Egr1 and Egr2 in thymic precursors of NKT cells.
Figure 2: Induction of Egr2 and Zbtb16 in thymocytes that had received signaling via TCRβ in vivo.
Figure 3: ChIP-seq analysis of Egr2-binding sites.
Figure 4: Egr2 binds and transactivates the Zbtb16 promoter.
Figure 5: Egr2 controls early and late NKT developmental checkpoints.
Figure 6: Egr2 is required for the activation of PLZF in NKT cell development.
Figure 7: Egr2 is required for the developmental transition from stage 2 to stage 3.

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  • 04 April 2012

    In the version of this article initially published, the fourth author's name lacked the middle initial. The correct name is Chauncey J. Spooner. The error has been corrected in the HTML and PDF versions of the article.

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Acknowledgements

We thank P. Charnay (Institut National de la Santé et de la Recherche Médicale) for Egr1-Egr2-deficient mice; E. Bartom for help with analysis of ChIP-seq data; M. Wang for help with statistical analyses; the University of Chicago Animal Resource Center, Core Flow Cytometry Facility, DNA Sequencing Facility; the National Institute of Allergy and Infectious Diseases tetramer facility for CD1d tetramers; and the ImmGen Consortium for data assembly. Supported by the US National Institutes of Health (AI038339 and AI053725; and T32AI0709030 to M.P.S.), the Digestive Disease Research Core Center (P30 DK42086), the Cancer Research Institute (R.M.) and the Howard Hughes Medical Institute (A.B.).

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  1. Chauncey J Spooner & Harinder Singh

    Present address: Present address: Department of Discovery Immunology, Genentech, South San Francisco, California, USA.,

Authors and Affiliations

  1. Committee on Immunology and The Howard Hughes Medical Institute, University of Chicago, Chicago, Illinois, USA

    Michael P Seiler, Rebecca Mathew, Megan K Liszewski, Chauncey J Spooner, Kenneth Barr, Fanyong Meng, Harinder Singh & Albert Bendelac

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Contributions

M.P.S. designed and did experiments and analyzed the data; R.M. did the ChIP-seq experiment in Figure 3; M.K.L. assisted with the experiments in Figure 1; C.J.S. and H.S. assisted with the design and interpretation of experiments and provided constructs, reagents and mouse strains; K.B. analyzed the ChIP-seq experiment in Figure 3; F.M. assisted with experiments; A.B. designed and supervised experiments and data analysis; and M.P.S. and A.B. wrote the manuscript.

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Correspondence to Albert Bendelac.

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Seiler, M., Mathew, R., Liszewski, M. et al. Elevated and sustained expression of the transcription factors Egr1 and Egr2 controls NKT lineage differentiation in response to TCR signaling. Nat Immunol 13, 264–271 (2012). https://doi.org/10.1038/ni.2230

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