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Insights into the biology and therapeutic implications of TNF and regulatory T cells

Nature Reviews Rheumatology volume 17, pages 487–504 (2021)Cite this article

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Abstract

Treatments that block tumour necrosis factor (TNF) have major beneficial effects in several autoimmune and rheumatic diseases, including rheumatoid arthritis. However, some patients do not respond to TNF inhibitor treatment and rare occurrences of paradoxical disease exacerbation have been reported. These limitations on the clinical efficacy of TNF inhibitors can be explained by the differences between TNF receptor 1 (TNFR1) and TNFR2 signalling and by the diverse effects of TNF on multiple immune cells, including FOXP3+ regulatory T cells. This basic knowledge sheds light on the consequences of TNF inhibitor therapies on regulatory T cells in treated patients and on the limitations of such treatment in the control of diseases with an autoimmune component. Accordingly, the next generation of drugs targeting TNF is likely to be based on agents that selectively block the binding of TNF to TNFR1 and on TNFR2 agonists. These approaches could improve the treatment of rheumatic diseases in the future.

Key points

  • Tumour necrosis factor (TNF) is a major inflammatory cytokine that has deleterious effects in several rheumatic and autoimmune diseases as attested by the success of TNF inhibitor therapy.

  • Some patients do not respond to TNF inhibitors and others develop paradoxical autoimmune exacerbations that can be explained by the immunoregulatory role of TNF.

  • The pro-inflammatory and anti-inflammatory properties of TNF are largely segregated by the capacity of this cytokine to bind to TNF receptor 1 (TNFR1) and TNFR2, respectively.

  • The anti-inflammatory effects of TNF are explained by its capacity to increase the proliferation, stability and suppressive function of FOXP3+ regulatory T cells via TNFR2 signalling.

  • Antagonists of TNFR1 and agonists of TNFR2 constitute a new generation of drugs that might be more effective and have fewer adverse effects than classical TNF inhibitors.

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Fig. 1: The pro-inflammatory and anti-inflammatory activities of TNF are driven by effects on innate and adaptive immunity.
Fig. 2: The overall effects of TNF on Treg cells.

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Acknowledgements

The author thanks current and past members of his laboratory for their hard work and fruitful and passionate exchanges on the effects of TNF on Treg cells. His research work is supported by Agence Nationale de la Recherche (grants ANR-15-CE15-0015-03 and ANR-17-CE15-0030-01) and Fondation pour la Recherche Médicale (équipe FRM).

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  1. Sorbonne Université, INSERM, CNRS, Centre d’Immunologie et des Maladies Infectieuses (CIMI-Paris), Paris, France

    Benoit L. Salomon

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B.L.S. declares that he received consultancy fees from HiFiBio Therapeutics regarding the applications of TNFR2 agonists and antagonists in cancer and autoimmunity.

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Salomon, B.L. Insights into the biology and therapeutic implications of TNF and regulatory T cells. Nat Rev Rheumatol 17, 487–504 (2021). https://doi.org/10.1038/s41584-021-00639-6

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