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Forkhead box transcription factors as context-dependent regulators of lymphocyte homeostasis

Nature Reviews Immunology volume 18, pages 703–715 (2018)Cite this article

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Abstract

Lymphocytes have evolved to react rapidly and robustly to changes in their local environment by using transient adaptations and by regulating their terminal differentiation programmes. Forkhead box transcription factors (FTFs) can direct leukocyte-specific responses, and their functional diversification promotes a high degree of context-dependent specification. Many, often antagonistic, FTFs have overlapping expression patterns and can thereby compete for binding to the same chromosomal target sequences. Multiple molecular mechanisms also connect extracellular signals to the expression and functionality of specific FTFs and, in this way, fine-tune their activity. Through these diverse mechanisms, FTFs can function as context-dependent rheostats responding to diverse environmental stimuli. Focusing on the various mechanisms by which their functional activity is modulated, as well as on their mechanisms of action, we discuss how specific FTFs control lymphocyte function, allowing for the establishment and maintenance of immune homeostasis.

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Fig. 1: Role of FTFs during B cell maturation and functioning.
Fig. 2: Role of FTFs during T cell maturation and functioning.
Fig. 3: FOXO-mediated regulation of T cell homing.
Fig. 4: Control of memory CD8+ T cell generation by FOXO1.
Fig. 5: Interactions between FTFs and cofactors in lymphocytes.
Fig. 6: Post-translational modifications control FTF transcriptional output.

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Acknowledgements

We would like to apologise to any authors whose work could not be cited due to space contstraints. The Zaiss laboratory is supported by the Medical Research Council, grant MR/M011755/1, and the European Union, grant CIG-631413 (“EGF-R for Immunity”). The Coffer laboratory is supported by grants from the Dutch Cancer Society (UU 2015-7838) and Dutch Reumatology Foundation (16-1-301)

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Nature Reviews Immunology thanks M. Suresh and the other anonymous reviewer(s) for their help with the peer review of this manuscript.

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Authors and Affiliations

  1. Institute of Immunology and Infection Research, School of Biological Sciences, University of Edinburgh, Edinburgh, UK

    Dietmar M. W. Zaiss

  2. Center for Molecular Medicine and Division of Pediatrics, UMC Utrecht, Utrecht University, Utrecht, Netherlands

    Paul J. Coffer

  3. Regenerative Medicine Center, UMC Utrecht, Utrecht University, Utrecht, Netherlands

    Paul J. Coffer

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Zaiss, D.M.W., Coffer, P.J. Forkhead box transcription factors as context-dependent regulators of lymphocyte homeostasis. Nat Rev Immunol 18, 703–715 (2018). https://doi.org/10.1038/s41577-018-0048-9

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