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.
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.
Department of Microbiology, Carver College of Medicine, University of Iowa, Iowa City, IA 52242.|Interdisciplinary Immunology Graduate Program, Carver College of Medicine, University of Iowa, Iowa City, IA 52242.
Farrah C
FC
Steinke
State Key Laboratory of Agrobiotechnology, College of Biological Sciences, China Agricultural University, Beijing, P. R. China 100193.
Shuyang
S
Yu
Insitute of Immunology, Third Military Medical University, Chongqing, P. R. China 400038.
Xinyuan
X
Zhou
Interdisciplinary Graduate Program in Genetics, Carver College of Medicine, University of Iowa, Iowa City, IA 52242.
Bing
B
He
Development Biology Center, NHLBI, NIH, Bethesda, MD 20892.
Wenjing
W
Yang
Department of Microbiology, Carver College of Medicine, University of Iowa, Iowa City, IA 52242.
Bo
B
Zhou
Department of Immunology, Institute for Frontier Medical Sciences, Kyoto University, Kyoto, Japan 606-8507.
Hiroshi
H
Kawamoto
Development Biology Center, NHLBI, NIH, Bethesda, MD 20892.
Jun
J
Zhu
Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, IA 52242.
Kai
K
Tan
Department of Microbiology, Carver College of Medicine, University of Iowa, Iowa City, IA 52242.|Interdisciplinary Immunology Graduate Program, Carver College of Medicine, University of Iowa, Iowa City, IA 52242.
Hai-Hui
HH
Xue
D000818:Animals; D015704:CD4 Antigens / Q000502:physiology*; D015496:CD4-Positive T-Lymphocytes / Q000502:physiology*; D018414:CD8-Positive T-Lymphocytes / Q000502:physiology*; D019070:Cell Lineage; D050677:Core Binding Factor Alpha 3 Subunit / Q000502:physiology*; D005260:Female; D051538:Hepatocyte Nuclear Factor 1-alpha; D051821:Lymphoid Enhancer-Binding Factor 1 / Q000502:physiology*; D008297:Male; D051379:Mice; D051822:T Cell Transcription Factor 1 / Q000502:physiology*; D014157:Transcription Factors / Q000502:physiology*
D015704:CD4 Antigens; D050677:Core Binding Factor Alpha 3 Subunit; D051538:Hepatocyte Nuclear Factor 1-alpha; D051821:Lymphoid Enhancer-Binding Factor 1; D051822:T Cell Transcription Factor 1; D014157:Transcription Factors; C496488:Hnf1a protein, mouse; C497574:Lef1 protein, mouse; C493730:Runx3 protein, mouse; C497211:Zbtb7b protein, mouse