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Nat Immunol. 2014 Jul;15(7):646-656. doi: 10.1038/ni.2897. Epub 2014 May 18.

TCF-1 and LEF-1 act upstream of Th-POK to promote the CD4(+) T cell fate and interact with Runx3 to silence Cd4 in CD8(+) T cells.

Author information

1
Department of Microbiology, Carver College of Medicine, University of Iowa, Iowa City, IA 52242.
2
Interdisciplinary Immunology Graduate Program, Carver College of Medicine, University of Iowa, Iowa City, IA 52242.
3
State Key Laboratory of Agrobiotechnology, College of Biological Sciences, China Agricultural University, Beijing, P. R. China 100193.
4
Insitute of Immunology, Third Military Medical University, Chongqing, P. R. China 400038.
5
Interdisciplinary Graduate Program in Genetics, Carver College of Medicine, University of Iowa, Iowa City, IA 52242.
6
Development Biology Center, NHLBI, NIH, Bethesda, MD 20892.
7
Department of Immunology, Institute for Frontier Medical Sciences, Kyoto University, Kyoto, Japan 606-8507.
8
Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, IA 52242.
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Contributed equally

Abstract

The transcription factors TCF-1 and LEF-1 are essential for early T cell development, but their roles beyond the CD4(+)CD8(+) double-positive (DP) stage are unknown. By specific ablation of these factors in DP thymocytes, we demonstrated that deficiency in TCF-1 and LEF-1 diminished the output of CD4(+) T cells and redirected CD4(+) T cells to a CD8(+) T cell fate. The role of TCF-1 and LEF-1 in the CD4-versus-CD8 lineage 'choice' was mediated in part by direct positive regulation of the transcription factor Th-POK. Furthermore, loss of TCF-1 and LEF-1 unexpectedly caused derepression of CD4 expression in T cells committed to the CD8(+) lineage without affecting the expression of Runx transcription factors. Instead, TCF-1 physically interacted with Runx3 to cooperatively silence Cd4. Thus, TCF-1 and LEF-1 adopted distinct genetic 'wiring' to promote the CD4(+) T cell fate and establish CD8(+) T cell identity.

PMID:
24836425
PMCID:
PMC4064003
DOI:
10.1038/ni.2897
[Indexed for MEDLINE]
Free PMC Article
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