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.

SUMMARY The TCF-1 and LEF-1 transcription factors are known to play critical roles in normal thymocyte development. Unexpectedly, we found that TCF-1-deficient (Tcf7−/−) mice developed aggressive T-cell malignancy, resembling human T-cell acute lymphoblastic leukemia (T-ALL). Surprisingly, LEF-1 was aberrantly upregulated in pre-malignant Tcf7−/− early thymocytes and lymphoma cells. We further demonstrated that TCF-1 directly repressed LEF-1 expression in early thymocytes and that conditional inactivation of Lef1 greatly delayed or prevented T-cell malignancy in Tcf7−/− mice. In human T-ALLs, an early thymic progenitor (ETP) subtype was associated with diminished TCF7 expression, and two of the ETP-ALL cases harbored TCF7 gene deletions. We also showed that TCF-1 and LEF-1 were dispensable for T-lineage commitment but instead were required for early thymocytes to mature beyond the CD4−CD8− stage. TCF-1 thus has dual roles, i.e., acting cooperatively with LEF-1 to promote thymocyte maturation while restraining LEF-1 expression to prevent malignant transformation of developing thymocytes.

No abstract

Transcription factors have recurring roles during T cell development and activation. Tcf1 and Lef1 are known to be essential for early stages of thymocyte maturation. Recent research has revealed several novel aspects of their functionality. Tcf1 is induced at the very earliest step of specifying hematopoietic progenitors to the T cell lineage as a key target gene downstream of Notch activation. In addition to promoting maturation of T-lineage-committed thymocytes, Tcf1 functions as a tumor suppressor in developing thymocytes, and this is mediated, paradoxically, by restraining Lef1 expression. After positive selection, Tcf1 and Lef1 act together to direct CD4(+)CD8(+) double positive thymocytes to a CD4(+) T cell fate. Although not required for CD8(+) T cell differentiation, Tcf1 and Lef1 cooperate with Runx factors to achieve stable silencing of the Cd4 gene in CD8(+) T cells. Tcf1 is also found to have versatile roles in innate immune cells, which partly mirror its functions in mature T helper cells. Discrepancy in requirements of Tcf1/Lef1 and β-catenin in T cells has been a long-standing enigma. We will review other protein factors interacting with Tcf1 and Lef1 and discuss their regulatory roles independent of β-catenin.

Natural killer T (NKT) cells develop from common CD4+ CD8+ thymocyte precursors. Transcriptional programs that regulate the development of NKT cells in the thymus development remain to be fully delineated. Here we demonstrate a cell-intrinsic requirement for transcription factors TCF1 and LEF1 for the development of all subsets of NKT cells. Conditional deletion of TCF1 alone results in a substantial reduction in NKT cells. The remaining NKT cells are eliminated when TCF1 and LEF1 are both deleted. These data reveal an essential role for TCF1 and LEF1 in development of NKT cells.