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Interleukin-2 and regulatory T cells in rheumatic diseases

Nature Reviews Rheumatology volume 17, pages 749–766 (2021)Cite this article

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Abstract

Failure of regulatory T (Treg) cells to properly control immune responses leads invariably to autoimmunity and organ damage. Decreased numbers or impaired function of Treg cells, especially in the context of inflammation, has been documented in many human autoimmune diseases. Restoration of Treg cell fitness and/or expansion of their numbers using low-dose natural IL-2, the main cytokine driving Treg cell survival and function, has demonstrated clinical efficacy in early clinical trials. Genetically modified IL-2 with an extended half-life and increased selectivity for Treg cells is now in clinical development. Administration of IL-2 combined with therapies targeting other pathways involved in the expression of autoimmune diseases should further enhance its therapeutic potential. Ongoing clinical efforts that capitalize on the early clinical success of IL-2 treatment should bring the use of this cytokine to the forefront of biological treatments for autoimmune diseases.

Key points

  • Dysregulation of regulatory T (Treg) cells and a consequent inability to correctly control immune responses leads invariably to autoimmunity and organ damage.

  • Numerical or functional impairment of Treg cells, especially in the context of inflammation, occurs in many human autoimmune diseases, such as rheumatoid arthritis and systemic lupus erythematosus (SLE).

  • Restoration of the immune balance by restoring Treg cell numbers and/or function is therefore the basis of therapeutic efforts to restore tolerance and mitigate tissue inflammation and injury.

  • Low-dose IL-2 (0.3–3 MIU daily in humans) is now an established therapy in autoimmune diseases; it stimulates mainly Treg cells and is well tolerated.

  • Most studies of low-dose IL-2 in SLE have shown a clinically significant improvement (as assessed by the SLE Disease Activity Index (SLEDAI) or the SLE Responder Index 4 (SRI-4)) and a reduction in concomitant prednisone of ≥50% in 44–67% of patients.

  • Genetically modified IL-2 proteins (‘muteins’) or IL-2–anti-IL-2R antibody complexes with an extended half-life and increased selectivity for Treg cells are now in clinical development.

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Fig. 1: IL-2 signalling pathways and formulations.
Fig. 2: Pathogenesis of seropositive RA and implications for IL-2 therapy.
Fig. 3: Pathogenesis of SLE and implications for IL-2 therapy.

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Author information

Authors and Affiliations

  1. Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA

    Antonios G. A. Kolios & George C. Tsokos

  2. Department of Dermatology, University Hospital Zurich, Zurich, Switzerland

    Antonios G. A. Kolios

  3. Sorbonne Université, INSERM, Immunology-Immunopathology-Immunotherapy (i3), Paris, France

    David Klatzmann

  4. AP-HP, Hôpital Pitié-Salpêtrière, Clinical Investigation Center for Biotherapies (CIC-BTi) and Immunology-Inflammation-Infectiology and Dermatology Department (3iD), Paris, France

    David Klatzmann

Authors
  1. Antonios G. A. Kolios
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  2. George C. Tsokos
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  3. David Klatzmann
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Contributions

The authors contributed equally to all aspects of the article.

Corresponding author

Correspondence to David Klatzmann.

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Competing interests

D.K. is an inventor of patents belonging to Sorbonne Université that cover the use of IL-2 in autoimmune diseases; he holds shares in ILTOO Pharma. A.G.A.K. and G.C.T. declare no competing interests.

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Nature Reviews Rheumatology thanks Z.-G. Li, J. Humrich, and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Kolios, A.G.A., Tsokos, G.C. & Klatzmann, D. Interleukin-2 and regulatory T cells in rheumatic diseases. Nat Rev Rheumatol 17, 749–766 (2021). https://doi.org/10.1038/s41584-021-00707-x

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