How transcription factors drive choice of the T cell fate

Abstract

Recent evidence has elucidated how multipotent blood progenitors transform their identities in the thymus and undergo commitment to become T cells. Together with environmental signals, a core group of transcription factors have essential roles in this process by directly activating and repressing specific genes. Many of these transcription factors also function in later T cell development, but control different genes. Here, we review how these transcription factors work to change the activities of specific genomic loci during early intrathymic development to establish T cell lineage identity. We introduce the key regulators and highlight newly emergent insights into the rules that govern their actions. Whole-genome deep sequencing-based analysis has revealed unexpectedly rich relationships between inherited epigenetic states, transcription factor–DNA binding affinity thresholds and influences of given transcription factors on the activities of other factors in the same cells. Together, these mechanisms determine T cell identity and make the lineage choice irreversible.

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Fig. 1: Early T cell developmental stages in mice.
Fig. 2: Major changes in epigenetic state and transcription factor expression in mouse pro-T cells.
Fig. 3: Conditionality of transcription factor binding at genomic sites.
Fig. 4: Transcription factor binding changes at key developmentally regulated loci.

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Acknowledgements

The authors thank M. Romero-Wolf for helpful discussions and suggestions, and J. Ungerbäck, X. Wang, M. A. Yui and present and former members of the Rothenberg group, whose helpful discussion and published and unpublished data were important for the ideas in this Review. The authors apologize to colleagues whose relevant work could not be cited owing to space constraints. The authors gratefully acknowledge support from the Japan Society for the Promotion of Science KAKENHI (grant number JP19H03692), the Mochida Memorial Foundation for Medical and Pharmaceutical Research, the Naito Foundation and the Takeda Science Foundation (to H.H.), and from the US Public Health Service (R01AI135200, R01HL119102, R01HD100039 and R01HD076915) and the Albert Billings Ruddock Professorship (to E.V.R).

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Glossary

Notch pathway

Notch designates a cell-surface receptor (NOTCH1–NOTCH4 family in mammals) that interacts with cell-bound ligands of the Delta (Delta-like in mammals) and Serrate (Jagged in mammals) families. Originally discovered through its potent role in fruit fly development, Notch signalling controls important embryological switch points for the generation of various cell types in organisms of all kinds.

Positive selection

Once immature thymocytes at the double-positive stage have expressed a complete T cell receptor-αβ (TCRαβ) complex, the cells are doomed to die unless that TCR can interact with cell-surface molecules on thymic epithelial cells. Positive selection is the TCR-dependent rescue of the cells from death and the choice of helper or killer fate that results from that rescue.

Negative selection

If the newly expressed T cell receptor (TCR) on double-positive and immature single-positive thymocytes interacts too strongly with surface molecules on thymic antigen-presenting cells, the thymocytes are induced to commit suicide rather than enabled to survive and mature. Negative selection designates this TCR stimulation-dependent suicide.

β-Selection

The first step of T cell development that depends on a form of the T cell receptor (TCR), in this case a special immature form of the TCR consisting of only a TCRβ chain plus an invariant pre-TCRα surrogate chain. This complex is generated when double-negative 3a (DN3a) thymocytes successfully rearrange the genes encoding the TCRβ chain, and its assembly is required to enable the cells to proliferate and differentiate further to become double-positive thymocytes.

WNT signalling

The WNT pathway is a multistep developmental signalling pathway, often involved in self-renewal of tissue stem cells and in embryonic pattern formation in many organisms. In mammals, a soluble ligand from the large WNT family binds to a cell-surface receptor (of the FZD family), which enables β-catenin to avoid degradation in the cytoplasm and translocate to the nucleus, where it becomes a co-activator for transcription factors of the TCF/LEF family.

SWI/SNF complex

A nucleosome remodelling protein complex in eukaryotic cells that generally opens chromatin to allow greater transcription factor access. This is thought to be an important step involved in transcriptional activation of many genes.

Nucleosome remodelling deacetylase complex

(NuRD complex). A nucleosome remodelling protein complex that is recruited by many transcription factors and is often involved in target gene repression. Although the histone deacetylase activity of the complex is often used for repression, the complex as a whole can be involved in various transcriptional regulatory activities.

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Hosokawa, H., Rothenberg, E.V. How transcription factors drive choice of the T cell fate. Nat Rev Immunol (2020). https://doi.org/10.1038/s41577-020-00426-6

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