A critical role for TCF-1 in T-lineage specification and differentiation

Abstract

The vertebrate thymus provides an inductive environment for T-cell development. Within the thymus, Notch signals are indispensable for imposing the T-cell fate on multipotential hematopoietic progenitors, but the downstream effectors that impart T-lineage specification and commitment are not well understood. Here we show that transcription factor, T-cell factor 1 (TCF-1), is a critical regulator in T-cell specification. TCF-1 is highly expressed in the earliest thymic progenitors, and its expression is upregulated by Notch signals. Most importantly, when TCF-1 is forcibly expressed in BM progenitors, it drives the development of T-lineage cells in the absence of T-inductive Notch1 signals. Further characterization of these TCF-1-induced cells revealed expression of many T-lineage genes, including T-cell specific transcription factors Gata3, Bcl11b, and components of the T-cell receptor. Our data suggest a model where Notch signals induce TCF-1, and TCF-1 in turn imprints the T-cell fate by upregulating expression of T-cell essential genes.

A Genome-Wide Analysis Identifies a Notch–RBP-Jκ–IL-7Rα Axis That Controls IL-17–Producing γδ T Cell Homeostasis in Mice

“…RBP-Jk deletion selectively decreased IL-22-producing NKp46 + IL-7Ra + ILCs in the lamina propria but not in the Peyer's patches (45). Epigenetic analysis revealed that IL-7Ra expression in ILC2 cells was directly regulated by TCF1, which was shown to be a direct target of the Notch-RBP-Jk pathway in T cells (46,47). In fact, we also found ICN1 binding on the promoter region (231 kb upstream from the TSS) of TCF1 in gd T cells (Fig.…”

TCF1 and LEF1 act as T-cell intrinsic HTLV-1 antagonists by targeting Tax

“…The roles of TCF1/LEF1 have been well established in the thymus; they are indispensable in driving T-cell development (37). Nevertheless, their functions in the periphery remain unknown.…”

Wnt4 regulates thymic cellularity through the expansion of thymic epithelial cells and early thymic progenitors

“…Furthermore, the absence of the transcription factor TCF1 (Tcf7), whose deletion has been shown to result in loss of canonical Wnt signaling in DN4 thymocytes and mature T lymphocytes, 38,39 had no impact on the accumulation of ETPs and DN2s in the OP9-DW4 cocultures ( Figure 3D). Although TCF1 is crucial for early T-cell development, 26,40 compelling evidence suggests that TCF1 is not acting as an effector of canonical Wnt signaling in early T-cell development. 38,40 Wnt4 regulates TEC numbers during fetal thymopoiesis and postnatal thymic expansion Although our results indicate that Wnt4 has a direct effect on ETP and DN2 numbers, such an early defect would not be sufficient to explain a 2-fold difference in total cellularity because it should be compensated for at later stages.…”