TCF-1 and LEF-1 act upstream of Th-POK to promote CD4(+) T cell lineage choice and cooperate with Runx3 to silence the Cd4 gene in CD8(+) T cells

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 in DP thymocytes, we demonstrated that deficiency in TCF-1 and LEF-1 diminished CD4(+) T cell output and redirected CD4(+) T cells to a CD8(+) T cell fate. The role of TCF-1 and LEF-1 in CD4-CD8 lineage choice was partly mediated by direct positive regulation of Th-POK. Furthermore, loss of TCF-1 and LEF-1 unexpectedly caused CD4 derepression in CD8(+) lineage-committed T cells without affecting the expression of Runx factors. Instead, TCF-1 physically interacted with Runx3 to cooperatively silence the Cd4 gene. Thus, TCF-1 and LEF-1 adopt distinct genetic wiring to program CD4(+) fate decision and establish CD8(+) T cell identity.