The Journal of Experimental Medicine
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Published online November 12, 2007
doi:10.1084/jem.20070863
The Journal of Experimental Medicine, Vol. 204, No. 12, 3003-3015
The Rockefeller University Press, 0022-1007 $30.00
© 2007 Albu et al.
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ARTICLE

 BCL11B is required for positive selection and survival of double-positive thymocytes

Diana I. Albu1, Dongyun Feng1, Debarati Bhattacharya1, Nancy A. Jenkins2, Neal G. Copeland2, Pentao Liu3, and Dorina Avram1

1 Center for Cell Biology and Cancer Research, Albany Medical College, Albany, NY 12208
2 Mouse Cancer Genetics Program, National Cancer Institute, National Institutes of Health, Frederick, MD 21702
3 The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1HH, England, UK

CORRESPONDENCE Dorina Avram: avramd{at}mail.amc.edu

Transcriptional control of gene expression in double-positive (DP) thymocytes remains poorly understood. We show that the transcription factor BCL11B plays a critical role in DP thymocytes by controlling positive selection of both CD4 and CD8 lineages. BCL11B-deficient DP thymocytes rearrange T cell receptor (TCR) {alpha}; however, they display impaired proximal TCR signaling and attenuated extracellular signal-regulated kinase phosphorylation and calcium flux, which are all required for initiation of positive selection. Further, provision of transgenic TCRs did not improve positive selection of BCL11B-deficient DP thymocytes. BCL11B-deficient DP thymocytes have altered expression of genes with a role in positive selection, TCR signaling, and other signaling pathways intersecting the TCR, which may account for the defect. BCL11B-deficient DP thymocytes also presented increased susceptibility to spontaneous apoptosis associated with high levels of cleaved caspase-3 and an altered balance of proapoptotic/prosurvival factors. This latter susceptibility was manifested even in the absence of TCR signaling and was only partially rescued by provision of the BCL2 transgene, indicating that control of DP thymocyte survival by BCL11B is nonredundant and, at least in part, independent of BCL2 prosurvival factors.

Abbreviations used: DP, double-positive; qRT-PCR, quantitative RT-PCR; SP, single-positive.

N. A. Jenkins and N.G. Copeland's present address is Institute of Molecular and Cell Biology, Proteos, Singapore 138673.


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