Knapp Research Center, Section of Rheumatology, Department of Medicine, University of Chicago, Chicago, IL, USA.
Department of Immunology, Mayo Clinic, Scottsdale, AZ, USA.
Nat Immunol. 2022 May;23(5):671-678. doi: 10.1038/s41590-022-01194-2. Epub 2022 Apr 29.
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.
T 细胞特异性 DNA 结合蛋白 TCF-1 是 T 细胞发育和功能的多个阶段和谱系的核心调节因子。由于它与 β-连环蛋白相互作用，TCF-1 一直被经典地视为经典 Wnt 信号的下游效应因子，尽管有强有力的证据表明存在 β-连环蛋白非依赖性的 TCF-1 功能。TCF-1 共同结合含有或缺乏其保守基序的可及调控区域，并与其他核因子合作，建立上下文相关的表观遗传和转录程序，这些程序对于 T 细胞发育以及调节对感染、自身免疫和癌症的免疫反应至关重要。尽管 TCF-1 主要与染色质可及性和基因表达的正调控相关，但 TCF-1 具有降低染色质可及性并从而抑制基因表达的潜力。此外，TCF-1 的结合使 DNA 弯曲，并影响全基因组的染色质构象。本综述讨论了 TCF-1 在 T 细胞发育和功能中的多种作用及其机制基础的当前理解。
