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

FC Steinke, S Yu, X Zhou, B He, W Yang, B Zhou… - Nature …, 2014 - nature.com
FC Steinke, S Yu, X Zhou, B He, W Yang, B Zhou, H Kawamoto, J Zhu, K Tan, HH Xue
Nature immunology, 2014nature.com
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 …
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.
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