Abstract
The discovery of FOXP3+ regulatory T (Treg) cells as a distinct cell lineage with a central role in regulating immune responses provided a deeper understanding of self-tolerance. The transcription factor FOXP3 serves a key role in Treg cell lineage determination and maintenance, but is not sufficient to enable the full potential of Treg cell suppression, indicating that other factors orchestrate the fine-tuning of Treg cell function. Moreover, FOXP3-independent mechanisms have recently been shown to contribute to Treg cell dysfunction. FOXP3 mutations in humans cause lethal fulminant systemic autoinflammation (IPEX syndrome). However, it remains unclear to what degree Treg cell dysfunction is contributing to the pathophysiology of common autoimmune diseases. In this Review, we discuss the origins of Treg cells in the periphery and the multilayered mechanisms by which Treg cells are induced, as well as the FOXP3-dependent and FOXP3-independent cellular programmes that maintain the suppressive function of Treg cells in humans and mice. Further, we examine evidence for Treg cell dysfunction in the context of common autoimmune diseases such as multiple sclerosis, inflammatory bowel disease, systemic lupus erythematosus and rheumatoid arthritis.
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Acknowledgements
The authors thank P. Coish for proofreading the manuscript.
Funding
This work was supported by grants to N.T.C. from the National Institute of Allergy and Infectious Diseases (NIAID)/National Institutes of Health (NIH) (T32 AI155387), to T.S.S. from the National Multiple Sclerosis Society (NMSS) (JF-2208-40314) and Race to Erase MS, and to D.A.H. from the NIH (U19 AI089992, R25 NS079193, P01 AI073748, U24 AI11867, R01 AI22220, UM 1HG009390, P01 AI039671, P50 CA121974 and R01 CA227473), NMSS (CA 1061−A-18 and RG-1802-30153), Nancy Taylor Foundation for Chronic Diseases and Race to Erase MS. The article’s contents are solely the responsibility of the authors and do not necessarily represent the official views of the NIAID or NIH.
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N.T.C. and T.S.S. wrote the manuscript with input from all authors. The article conception and overall direction were initiated by T.S.S. and D.A.H., who were responsible for the strategic planning. All authors made substantial contributions to the article and collectively endorsed the final submitted version.
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D.A.H. has received research funding from Bristol-Myers Squibb, Novartis, Sanofi and Genentech, and has been a consultant for Bayer Pharmaceuticals, Repertoire, Bristol-Myers Squibb, Compass Therapeutics, EMD Serono, Genentech, Juno therapeutics, Novartis Pharmaceuticals, Proclara Biosciences, Sage Therapeutics and Sanofi Genzyme.
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Sumida, T.S., Cheru, N.T. & Hafler, D.A. The regulation and differentiation of regulatory T cells and their dysfunction in autoimmune diseases. Nat Rev Immunol (2024). https://doi.org/10.1038/s41577-024-00994-x
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DOI: https://doi.org/10.1038/s41577-024-00994-x
