TCF-1: a maverick in T cell development and function

Abstract

The T cell-specific DNA-binding protein TCF-1 is a central regulator of T cell development and function along multiple stages and lineages. Because it interacts with β-catenin, TCF-1 has been classically viewed as a downstream effector of canonical Wnt signaling, although there is strong evidence for β-catenin-independent TCF-1 functions. TCF-1 co-binds accessible regulatory regions containing or lacking its conserved motif and cooperates with other nuclear factors to establish context-dependent epigenetic and transcription programs that are essential for T cell development and for regulating immune responses to infection, autoimmunity and cancer. Although it has mostly been associated with positive regulation of chromatin accessibility and gene expression, TCF-1 has the potential to reduce chromatin accessibility and thereby suppress gene expression. In addition, the binding of TCF-1 bends the DNA and affects the chromatin conformation genome wide. This Review discusses the current understanding of the multiple roles of TCF-1 in T cell development and function and their mechanistic underpinnings.

Figure 1:. T cell development and the stages of TCF-1 implication.

Notch signaling upregulates Tcf7 expression in early ETPs ^–. TCF-1 induces the expression of genes encoding transcription factors critical for T cell specification, including Gata3 and Bcl11b. The levels of TCF-1 increases progressively up to the CD4⁺CD8⁺ (DP) stage. In CD4⁺CD8⁺ (DP) thymocytes TCF-1 cooperates with HEB to define their epigenetic landscape and trasncription profile . Following thymic selection the DP cells become either CD4⁺ or CD8⁺ SP cells. TCF-1 fosters the CD4⁺ T cell fate by promoting Zbtb7b (T_H-POK) expression, and although TCF-1 is not required for commitment to the CD8⁺ T cell lineage it ensures CD8⁺ T cell stability by cooperating with RUNX3 to suppress Cd4 gene expression . TCF-1 also suppresses Rorc (RORγT) and Il17 expression in DP thymocytes preventing their conversion to CD4⁺ T_H17 and CD8⁺ T_C17 cells ^,. After thymic egress CD4⁺ T cells differentiate into T_H subsets. TCF-1 promotes T_FH differentiation by inducing Bcl6 and supressing Prdm1 (BLIMP-1) expression and limits T_H1 differentiation by suppressing Tbx21 (T-bet) expression ^–. TCF-1 promotes T_H2 differentiation by directly upregulating Gata3 . TCF-1 is expressed by stem cell-like CD27⁺ T_H17 cells, which persist in models of MS . In T_REG cell subsets, TCF-1 cooperates with Foxp3 to limit expression of T cell activation and T_H17 differentiation genes. It also enhances Bcl6 expression to promote T_FR differentiation. CD8⁺ T cells are critical for defense against acute and chronic viral infections and cancers. In acute viral infection TCF-1 is important in driving the development of T_MP and T_MEM cells. Both in acute and chronic LCMV infection downregulation of TCF-1 is needed for the differentiation of T_EFF and T_EX cells. In chronic viral infections and cancer, TCF-1 and BCL-6 support the differentiation and maintenance of T_EX-_STEM cells that express PD-1 and can respond to anti-PD-1 therapy.

Figure 2.. Understanding the fundamental molecular functions of TCF-1.

TCF-1 has multiple molecular functions that are superimposed on its’ ability to bend the DNA upon binding and regulate the 3D chromatin conformation. (a) In the absence of β-catenin, TCF-1 can bind with the repressors of the Grg/TLE family at a region proximal to the HMG DNA binding domain ^, to reduce chromatin accessibility, and suppress gene transcription . Extracellular Wnts stabilize β-catenin by disrupting its’ degradatioin complex, allowing its’ nuclear translocation and interaction with the full-length TCF-1 protein. This results in the recruitment of epigenetic and transcription regulators that enhance chromatin accessibility and gene transcription. (b) TCF-1 cooperates with other transcription factors to establish context and developmental stage-specific epigenetic and transcription profiles through co-binding to common DNA sites. (c) TCF-1 could function as a pioneer-like factor and initiates changes in the chromatin landscape that establish the T cell lineage identity. (d,e) TCF-1 may function as a “Place Holder”, to promote/maintain T cell-specific chromatin accessibility, independently of Wnt signals. (f) TCF-1 has intrinsic histone deacetylase activity (HDAC) and can directly reduce chromatin accessibility.