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  • Review Article
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RUNX proteins in transcription factor networks that regulate T-cell lineage choice

Nature Reviews Immunology volume 9, pages 106–115 (2009)Cite this article

Key Points

  • This Review focuses on the transcriptional control of lineage decisions during T-cell development. In particular, current progress in our understanding of the transcription factor network that regulates CD4/CD8 lineage choice is highlighted.

  • Recent work indicates that the specification of positively selected thymocytes to either the CD4 or CD8 lineage is a reversible step, but that lineage commitment is the subsequent irreversible step that determines T-cell fate.

  • The transcription factors MYB, GATA-binding protein 3 (GATA3) and thymocyte selection-associated high-mobility group box (TOX) are lineage-specifying factors that cannot themselves enforce lineage choice, whereas RUNX (runt-related transcription factor) proteins and Th-POK (T-helper-inducing POZ/Kruppel-like factor) are lineage commitment factors that repress the development of the alternative fate.

  • Genetic studies have allowed the identification of enhancer and silencer elements in genes that are important for determining the fate of developing T cells, including Cd4, Cd8 and Zbtb7b (which encodes Th-POK). The binding of key transcription factors determines the activity of enhancer and silencer elements, thereby influencing gene expression and determining lineage choice. In this way, Th-POK has a role in commitment to the CD4 lineage, whereas RUNX3 is important for commitment to the CD8 lineage.

  • RUNX proteins also have a role in directing the differentiation of naive CD4+ T cells into different subsets of helper and regulatory T cells, and evidence suggests that the molecular mechanisms by which RUNX proteins regulate T-cell fate decisions are conserved between the thymus and periphery.

Abstract

Recent research has uncovered complex transcription factor networks that control the processes of T-cell development and differentiation. RUNX (runt-related transcription factor) proteins are among the many factors that have crucial roles in these networks. In this Review, we examine the mechanisms by which RUNX complexes act together with other transcription factors, such as Th-POK (T-helper-inducing POZ/Kruppel-like factor) and GATA-binding protein 3 (GATA3) in determining the CD4/CD8 lineage choice of developing thymocytes. In addition, we discuss evidence indicating that RUNX complexes are also involved in the differentiation of effector T-cell subsets and that the molecular mechanisms by which RUNX proteins regulate T-cell fate decisions are conserved between the thymus and periphery.

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Figure 1: The structure of Cd4 and Cd8 loci, illustrating important cis-acting elements.
Figure 2: The structure of the Zbtb7b locus, illustrating important cis-acting elements.
Figure 3: The transcription factor network that underlies T-cell lineage choice.
Figure 4: Transcription factor networks that underlie the differentiation of peripheral naive CD4+ T cells into T-helper- and regulatory T-cell subsets.

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Acknowledgements

We thank our many colleagues who have contributed to the study of T-cell lineage choice and apologize for not including all references in this Review owing to space limitations. We are grateful to the members of our laboratories for helpful discussion. The work of I.T. was supported by grants from Precursory Research for Embryonic Science and Technology (PREST) and the Japan Science and Technology Agency (JST). The work of D.R.L. was supported by a grant from the Howard Hughes Medical Institute.

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Authors and Affiliations

  1. The Kimmel Center for Biology and Medicine at the Skirball Institute of Biomolecular Medicine, Howard Hughes Medical Institute, New York University School of Medicine, 540 First Avenue, New York, 10016, New York, USA

    Amélie Collins & Dan R. Littman

  2. Laboratory for Transcriptional Regulation, RIKEN Research Center for Allergy and Immunology, 1-7-22 Suehiro-cho, Turumi-ku, Yokohama, 230-0045, Kanagawa, Japan

    Ichiro Taniuchi

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  1. Amélie Collins
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Glossary

β-selection

A process that, through a cell-autonomous signalling cascade, leads to the proliferation, differentiation and survival of thymocytes that have successfully recombined the β-chain of the T-cell receptor (TCR) locus to express a functional pre-TCR on their cell surface.

DNase hypersensitivity mapping

A technique that is used to investigate DNA regions that are likely to have regulatory roles in gene expression. It is based on the fact that the chromatin at regulatory regions is less condensed than at neighbouring regions, reflecting the need for increased accessibility to transcription factors, which results in higher sensitivity to digestion by endonucleases.

ChIP-on-chip

A technique that combines chromatin immunoprecipitation, which determines the binding of transcription factors to specific regions of genomic DNA, with microarray chips to determine the binding of transcription factors in a genome-wide, unbiased manner.

Hypomorphic mutant allele

A type of mutation in which either the altered gene product has a decreased level of activity or the wild-type gene product is expressed at a decreased level.

CRE recombinase

A site-specific recombination system. Two short DNA sequences (loxP sites) are engineered to flank the target DNA. Expression of the recombinase CRE leads to excision of the intervening sequence. Depending on the type of promoter that controls CRE expression, CRE can be expressed at specific times during development or by specific subsets of cells.

TH17 cell

A subset of CD4+ T helper (TH) cells that produce interleukin-17 (IL-17) and that are thought to be important in inflammatory and autoimmune diseases. Their generation involves IL-23 and IL-21, as well as the transcription factors retinoic-acid-receptor-related orphan receptor-γt and signal transducer and activator of transcription 3.

Regulatory T (TReg) cell

A specialized type of CD4+ T cell that can suppress the responses of other T cells. TReg cells provide a crucial mechanism for the maintenance of peripheral self tolerance and are characterized by the expression of CD25 (also known as the α-chain of the interleukin-2 receptor) and the transcription factor forkhead box P3.

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Collins, A., Littman, D. & Taniuchi, I. RUNX proteins in transcription factor networks that regulate T-cell lineage choice. Nat Rev Immunol 9, 106–115 (2009). https://doi.org/10.1038/nri2489

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