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TCF1 in T cell immunity: a broadened frontier

Abstract

TCF1 and its homologue LEF1 are historically known as effector transcription factors downstream of the WNT signalling pathway and are essential for early T cell development. Recent advances bring TCF1 into the spotlight for its versatile, context-dependent functions in regulating mature T cell responses. In the cytotoxic T cell lineages, TCF1 is required for the self-renewal of stem-like CD8+ T cells generated in response to viral or tumour antigens, and for preserving heightened responses to checkpoint blockade immunotherapy. In the helper T cell lineages, TCF1 is indispensable for the differentiation of T follicular helper and T follicular regulatory cells, and crucially regulates immunosuppressive functions of regulatory T cells. Mechanistic investigations have also identified TCF1 as the first transcription factor that directly modifies histone acetylation, with the capacity to bridge transcriptional and epigenetic regulation. TCF1 also has the potential to become an important clinical biomarker for assessing the prognosis of tumour immunotherapy and the success of viral control in treating HIV and hepatitis C virus infection. Here, we summarize the key findings on TCF1 across the fields of T cell immunity and reflect on the possibility of exploring TCF1 and its downstream transcriptional programmes as therapeutic targets for improving antiviral and antitumour immunity.

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Fig. 1: TCF1/LEF1 and their known cofactors.
Fig. 2: TCF1-dependent regulatory circuits during thymic development.
Fig. 3: TCF1-dependent regulatory circuits that modulate CD4+ T cell differentiation.
Fig. 4: TCF1 marks and instructs key CD8+ T cell differentiation processes.

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Contributions

X.Z. and H.-H.X. researched data for the article; Q.S. contributed substantially to discussion of the content; X.Z. and H.-H.X. wrote the article. All authors reviewed and/or edited the manuscript before submission.

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Correspondence to Hai-Hui Xue.

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Nature Reviews Immunology thanks I. Taniuchi and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Related links

Connectivity Map database: https://clue.io/cmap

Glossary

β-Catenin

A transcriptional co-activator that is post-translationally stabilized by activation of the WNT signalling pathway, and that engages multiple transcription factors including the TCF/LEF family for target gene regulation.

WNT signalling pathway

A signalling pathway that is initiated by WNT glycoprotein-mediated stimulation of Frizzled receptors, and leads to activation of β-catenin, calcium and/or planar cell polarity signalling cascades depending on the WNT ligands and cell context.

Pseudo-temporal reconstruction

A computational method of analysis of single-cell transcriptome by ordering individual cells based on the gradual transition of transcriptomic changes during differentiation processes, as if the cells are placed on a time axis.

ATAC-seq analysis

Assay for transposase-accessible chromatin using sequencing (ATAC-seq) is a method that uses the ability of transposase to access open regions in the genome and hence determines chromatin accessibility as a mechanism for gene expression.

Motif-based transcriptional activity projection

A computational method for the analysis of genome sequences with specific features, such as association with chromatin accessibility or histone marks, to predict direct binding and regulation by transcription factors based on their known consensus binding motifs.

BCL-6–BLIMP1 axis

A regulatory circuit whereby the transcription factors BCL-6 and BLIMP1 show recurrent, mutually antagonistic, effects, as observed in germinal cell B cell versus plasma cell, T follicular helper versus T helper 1 cell and TEX-stem versus TEX-term cell differentiation processes.

Granzymes

A group of proteases that are secreted by activated cytotoxic CD8+ T cells and natural killer cells that have the capacity to directly lyse intracellular pathogens and induce apoptosis of cells infected with intracellular pathogens.

EOMES–IL-2Rβ axis

A regulatory circuit in which the transcription factor EOMES positively regulates the expression of the IL-2 receptor β-chain and thus determines the responsiveness to the cytokines IL-2 and IL-15, as observed in effector and memory CD8+ T cells.

Connectivity Map database

An online resource maintained by the Broad Institute, which consists of genome-scale libraries that catalogue transcriptional responses to chemical, genetic and disease perturbations, and which can be explored for discovery of novel therapeutics. See Related links.

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Zhao, X., Shan, Q. & Xue, HH. TCF1 in T cell immunity: a broadened frontier. Nat Rev Immunol (2021). https://doi.org/10.1038/s41577-021-00563-6

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