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IKK2 controls the inflammatory potential of tissue-resident regulatory T cells in a murine gain of function model

Author

Listed:
  • Chelisa Cardinez

    (Australian National University
    The Canberra Hospital
    Australian National University
    Australian National University)

  • Yuwei Hao

    (Australian National University
    The Canberra Hospital
    Australian National University
    University of Cambridge)

  • Kristy Kwong

    (Australian National University
    The Canberra Hospital
    Australian National University
    University of Cambridge)

  • Ainsley R. Davies

    (Australian National University
    The Canberra Hospital
    Australian National University)

  • Morgan B. Downes

    (Australian National University
    The Canberra Hospital
    Australian National University)

  • Nadia A. Roberts

    (Australian National University)

  • Jason D. Price

    (Australian National University)

  • Raquel A. Hernandez

    (Australian National University
    The Canberra Hospital
    Australian National University)

  • Jessica Lovell

    (Australian National University)

  • Rochna Chand

    (Australian National University
    The Canberra Hospital
    Australian National University)

  • Zhi-Ping Feng

    (Australian National University)

  • Anselm Enders

    (Australian National University
    Australian National University)

  • Carola G. Vinuesa

    (Australian National University
    Francis Crick Institute)

  • Bahar Miraghazadeh

    (Australian National University
    The Canberra Hospital
    Australian National University)

  • Matthew C. Cook

    (Australian National University
    The Canberra Hospital
    Australian National University
    University of Cambridge)

Abstract

Loss-of-function mutations have provided crucial insights into the immunoregulatory actions of Foxp3+ regulatory T cells (Tregs). By contrast, we know very little about the consequences of defects that amplify aspects of Treg function or differentiation. Here we show that mice heterozygous for an Ikbkb gain-of-function mutation develop psoriasis. Doubling the gene dose (IkbkbGoF/GoF) results in dactylitis, spondylitis, and characteristic nail changes, which are features of psoriatic arthritis. IkbkbGoF mice exhibit a selective expansion of Foxp3 + CD25+ Tregs of which a subset express IL-17. These modified Tregs are enriched in both inflamed tissues, blood and spleen, and their transfer is sufficient to induce disease without conventional T cells. Single-cell transcriptional and phenotyping analyses of isolated Tregs reveal expansion of non-lymphoid tissue (tissue-resident) Tregs expressing Th17-related genes, Helios, tissue-resident markers including CD103 and CD69, and a prominent NF-κB transcriptome. Thus, IKK2 regulates tissue-resident Treg differentiation, and overactivity drives dose-dependent skin and systemic inflammation.

Suggested Citation

  • Chelisa Cardinez & Yuwei Hao & Kristy Kwong & Ainsley R. Davies & Morgan B. Downes & Nadia A. Roberts & Jason D. Price & Raquel A. Hernandez & Jessica Lovell & Rochna Chand & Zhi-Ping Feng & Anselm En, 2024. "IKK2 controls the inflammatory potential of tissue-resident regulatory T cells in a murine gain of function model," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-45870-3
    DOI: 10.1038/s41467-024-45870-3
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    References listed on IDEAS

    as
    1. Marc A. Gavin & Jeffrey P. Rasmussen & Jason D. Fontenot & Valeria Vasta & Vincent C. Manganiello & Joseph A. Beavo & Alexander Y. Rudensky, 2007. "Foxp3-dependent programme of regulatory T-cell differentiation," Nature, Nature, vol. 445(7129), pages 771-775, February.
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    3. Colby Zaph & Amy E. Troy & Betsy C. Taylor & Lisa D. Berman-Booty & Katherine J. Guild & Yurong Du & Evan A. Yost & Achim D. Gruber & Michael J. May & Florian R. Greten & Lars Eckmann & Michael Karin , 2007. "Epithelial-cell-intrinsic IKK-β expression regulates intestinal immune homeostasis," Nature, Nature, vol. 446(7135), pages 552-556, March.
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    5. Ye Zheng & Ashutosh Chaudhry & Arnold Kas & Paul deRoos & Jeong M. Kim & Tin-Tin Chu & Lynn Corcoran & Piper Treuting & Ulf Klein & Alexander Y. Rudensky, 2009. "Regulatory T-cell suppressor program co-opts transcription factor IRF4 to control TH2 responses," Nature, Nature, vol. 458(7236), pages 351-356, March.
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