Abstract
It is established that the transcription factor E2A and its antagonist Id3 modulate the checkpoints consisting of the precursor to the T cell antigen receptor (pre-TCR) and the TCR. Here we demonstrate that Id3 expression was higher beyond the pre-TCR checkpoint, remained high in naive T cells and showed a bimodal pattern in the effector-memory population. We show how E2A promoted T lineage specification and how pre-TCR-mediated signaling affected E2A genome-wide occupancy. Thymi in Id3-deficient mice had aberrant development of effector-memory cells, higher expression of the chemokine receptor CXCR5 and the transcriptional repressor Bcl-6 and, unexpectedly, T cell–B cell conjugates and B cell follicles. Collectively, our data show how E2A acted globally to orchestrate development into the T lineage and that Id3 antagonized E2A activity beyond the pre-TCR checkpoint to enforce the naive fate of T cells.
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Change history
25 June 2012
In the version of this article initially published, the GEO accession code for the ChIP–Seq data set was not included. The code is GSE30518. The error has been corrected in the HTML and PDF versions of the article.
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Acknowledgements
We thank A. Goldrath and members of the Murre laboratory for critical reading of the manuscript; G. Hardiman, M. Harabaglia, J. Sprague and C. Ludka for help with Solexa DNA sequencing; N. Varki and the University of California, San Diego Histology Core for histology; and Y. Zhuang (Duke University) for E2a/GFP and E2af/f mice. Supported by the American Recovery and Investment Act (27775A to Y.C.L.) and the US National Institutes of Health (C.M.).
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M.M. designed and did experiments, analyzed data and wrote portions of the manuscript; R.R.R. generated Id3-GFP mice; K.M. did ChIP analyses; Y.C.L. contributed to the analysis of data from ChIP followed by deep sequencing; Y.A. provided advice on ChIP experiments with small number of cells; and C.M. designed experiments, analyzed data and wrote the manuscript.
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Miyazaki, M., Rivera, R., Miyazaki, K. et al. The opposing roles of the transcription factor E2A and its antagonist Id3 that orchestrate and enforce the naive fate of T cells. Nat Immunol 12, 992–1001 (2011). https://doi.org/10.1038/ni.2086
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DOI: https://doi.org/10.1038/ni.2086
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