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

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 Enders, Carola G. Vinuesa, Bahar Miraghazadeh and Matthew C. Cook ()
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Chelisa Cardinez: Australian National University
Yuwei Hao: Australian National University
Kristy Kwong: Australian National University
Ainsley R. Davies: Australian National University
Morgan B. Downes: Australian National University
Nadia A. Roberts: Australian National University
Jason D. Price: Australian National University
Raquel A. Hernandez: Australian National University
Jessica Lovell: Australian National University
Rochna Chand: Australian National University
Zhi-Ping Feng: Australian National University
Anselm Enders: Australian National University
Carola G. Vinuesa: Australian National University
Bahar Miraghazadeh: Australian National University
Matthew C. Cook: Australian National University

Nature Communications, 2024, vol. 15, issue 1, 1-17

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-45870-3

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