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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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.).
The authors declare no competing financial interests.
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