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Novel Foxo1-dependent transcriptional programs control Treg cell function

Author

Listed:
  • Weiming Ouyang

    (Immunology Program, Memorial Sloan-Kettering Cancer Center)

  • Will Liao

    (Cold Spring Harbor Laboratory
    Stony Brook University)

  • Chong T. Luo

    (Immunology Program, Memorial Sloan-Kettering Cancer Center
    Louis V. Gerstner, Jr Graduate School of Biomedical Sciences, Memorial Sloan-Kettering Cancer Center)

  • Na Yin

    (Immunology Program, Memorial Sloan-Kettering Cancer Center)

  • Morgan Huse

    (Immunology Program, Memorial Sloan-Kettering Cancer Center)

  • Myoungjoo V. Kim

    (Immunology Program, Memorial Sloan-Kettering Cancer Center)

  • Min Peng

    (Immunology Program, Memorial Sloan-Kettering Cancer Center)

  • Pamela Chan

    (Immunology Program, Memorial Sloan-Kettering Cancer Center)

  • Qian Ma

    (Immunology Program, Memorial Sloan-Kettering Cancer Center)

  • Yifan Mo

    (Cold Spring Harbor Laboratory
    Stony Brook University)

  • Dies Meijer

    (Erasmus University Medical Center, 3000 DR Rotterdam, The Netherlands)

  • Keji Zhao

    (Systems Biology Center, NHLBI, National Institute of Health)

  • Alexander Y. Rudensky

    (Immunology Program, Memorial Sloan-Kettering Cancer Center
    Howard Hughes Medical Institute, Memorial Sloan-Kettering Cancer Center)

  • Gurinder Atwal

    (Cold Spring Harbor Laboratory)

  • Michael Q. Zhang

    (Center for Systems Biology, The University of Texas at Dallas
    Center for Synthetic and Systems Biology, TNLIST, Tsinghua University, Beijing 100084, China)

  • Ming O. Li

    (Immunology Program, Memorial Sloan-Kettering Cancer Center)

Abstract

Regulatory T (Treg) cells, characterized by expression of the transcription factor forkhead box P3 (Foxp3), maintain immune homeostasis by suppressing self-destructive immune responses1,2,3,4. Foxp3 operates as a late-acting differentiation factor controlling Treg cell homeostasis and function5, whereas the early Treg-cell-lineage commitment is regulated by the Akt kinase and the forkhead box O (Foxo) family of transcription factors6,7,8,9,10. However, whether Foxo proteins act beyond the Treg-cell-commitment stage to control Treg cell homeostasis and function remains largely unexplored. Here we show that Foxo1 is a pivotal regulator of Tregcell function. Treg cells express high amounts of Foxo1 and display reduced T-cell-receptor-induced Akt activation, Foxo1 phosphorylation and Foxo1 nuclear exclusion. Mice with Treg-cell-specific deletion of Foxo1 develop a fatal inflammatory disorder similar in severity to that seen in Foxp3-deficient mice, but without the loss of Treg cells. Genome-wide analysis of Foxo1 binding sites reveals ∼300 Foxo1-bound target genes, including the pro-inflammatory cytokine Ifng, that do not seem to be directly regulated by Foxp3. These findings show that the evolutionarily ancient Akt–Foxo1 signalling module controls a novel genetic program indispensable for Treg cell function.

Suggested Citation

  • Weiming Ouyang & Will Liao & Chong T. Luo & Na Yin & Morgan Huse & Myoungjoo V. Kim & Min Peng & Pamela Chan & Qian Ma & Yifan Mo & Dies Meijer & Keji Zhao & Alexander Y. Rudensky & Gurinder Atwal & M, 2012. "Novel Foxo1-dependent transcriptional programs control Treg cell function," Nature, Nature, vol. 491(7425), pages 554-559, November.
  • Handle: RePEc:nat:nature:v:491:y:2012:i:7425:d:10.1038_nature11581
    DOI: 10.1038/nature11581
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    1. Eileen Rauch & Timm Amendt & Aleksandra Lopez Krol & Fabian B. Lang & Vincent Linse & Michelle Hohmann & Ann-Christin Keim & Susanne Kreutzer & Kevin Kawengian & Malte Buchholz & Philipp Duschner & Sa, 2024. "T-bet+ B cells are activated by and control endogenous retroviruses through TLR-dependent mechanisms," Nature Communications, Nature, vol. 15(1), pages 1-19, December.
    2. Di Wu & Haomin Li & Mingwei Liu & Jun Qin & Yi Sun, 2022. "The Ube2m-Rbx1 neddylation-Cullin-RING-Ligase proteins are essential for the maintenance of Regulatory T cell fitness," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
    3. Aurélie Durand & Nelly Bonilla & Théo Level & Zoé Ginestet & Amélie Lombès & Vincent Guichard & Mathieu Germain & Sébastien Jacques & Franck Letourneur & Marcio Cruzeiro & Carmen Marchiol & Gilles Ren, 2024. "Type 1 interferons and Foxo1 down-regulation play a key role in age-related T-cell exhaustion in mice," Nature Communications, Nature, vol. 15(1), pages 1-19, December.
    4. Srikanth Sadhu & Rajdeep Dalal & Jyotsna Dandotiya & Akshay Binayke & Virendra Singh & Manas Ranjan Tripathy & Vinayaka Das & Sandeep Goswami & Shakti Kumar & Zaigham Abbas Rizvi & Amit Awasthi, 2023. "IL-9 aggravates SARS-CoV-2 infection and exacerbates associated airway inflammation," Nature Communications, Nature, vol. 14(1), pages 1-16, December.

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