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Review
. 2025 Jan;21(1):9-21.
doi: 10.1038/s41584-024-01190-w. Epub 2024 Dec 9.

The 'Treg paradox' in inflammatory arthritis

Julia T Schnell  1   2 , Raquel Laza Briviesca  3 , Taehyeung Kim  3 , Louis-Marie Charbonnier  3 , Lauren A Henderson  3 , Femke van Wijk  4 , Peter A Nigrovic  5   6
Affiliations
Review

The 'Treg paradox' in inflammatory arthritis

Julia T Schnell et al. Nat Rev Rheumatol. 2025 Jan.

Abstract

Classic regulatory T (Treg) cells expressing CD4 and the hallmark transcription factor FOXP3 are integral to the prevention of multi-system autoimmunity. However, immune-mediated arthritis is often associated with increased numbers of Treg cells in the inflamed joints. To understand these seemingly conflicting observations, which we collectively describe as 'the Treg paradox', we provide an overview of Treg cell biology with a focus on Treg cell heterogeneity, function and dysfunction in arthritis. We discuss how the inflamed environment constrains the immunosuppressive activity of Treg cells while also promoting the differentiation of TH17-like Treg cell, exTreg cell (effector T cells that were formerly Treg cells), and osteoclastogenic Treg cell subsets that mediate tissue injury. We present a new framework to understand Treg cells in joint inflammation and define potential strategies for Treg cell-directed interventions in human inflammatory arthritis.

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Conflict of interest statement

Competing interests: L.A.H. has received salary support from the Childhood Arthritis and Rheumatology Research Alliance (CARRA); investigator-initiated research grants from BMS; and consulting fees from Sobi, Pfizer and Adaptive Biotechnologies. F.v.W. has previously served as a speaker and/or consultant for Janssen, Johnson & Johnson and Takeda, and has received grants from Regeneron Pharmaceuticals, LEO Pharma, Sanofi, BMS, Galapagos and Takeda. P.A.N. declares consulting relationships with Alkermes, Apollo, BMS, Exo Therapeutics, Fresh Tracks Therapeutics, Merck, Novartis, Pfizer, Qiagen and Sobi; equity in Edelweiss Immune Inc.; investigator-initiated research grants from BMS and Pfizer; and authorship and editorial income from UpToDate, the American Academy of Paediatrics and Arthritis & Rheumatology. All other authors declare no competing interests.

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