How transcription factors drive choice of the T cell fate

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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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X. Wang, M. A. Yui and present and former members of the Rothenberg group, whose helpful discussion and published and unpublished data were important for the ideas in this Review.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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Authors and Affiliations

  1. Department of Immunology, Tokai University School of Medicine, Isehara, Kanagawa, Japan Hiroyuki Hosokawa
  2. Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA, USA Hiroyuki Hosokawa & Ellen V. Rothenberg