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  • Review Article
  • Published:

Interleukin-21: a double-edged sword with therapeutic potential

Nature Reviews Drug Discovery volume 13, pages 379–395 (2014)Cite this article

Subjects

Key Points

  • Interleukin-21 (IL-21) is a pleiotropic cytokine with actions on a broad range of lymphoid, myeloid and epithelial cells. These actions include effects on proliferation, survival, differentiation and function.

  • IL-21 has a key role in B cell differentiation to plasma cells and in the development of T follicular helper cells, promoting functional germinal centres and immunoglobulin production.

  • IL-21 induces a functional programme in CD8+ T cells that leads to enhanced survival, antiviral activity and antitumour activity.

  • IL-21 has a key role in the development of T helper 17 (TH17) cells, which contribute to pathogenesis in a range of inflammatory diseases.

  • Clinical trials with IL-21 alone or in combination with other agents have yielded favourable results in the treatment of solid tumours.

  • IL-21 promotes a range of autoimmune diseases, including systemic lupus erythematosus, type 1 diabetes, multiple sclerosis, inflammatory bowel disease and psoriasis. Clinical trials using IL-21 inhibitors are in progress.

Abstract

Interleukin-21 is a cytokine with broad pleiotropic actions that affect the differentiation and function of lymphoid and myeloid cells. Since its discovery in 2000, a tremendous amount has been learned about its biological actions and the molecular mechanisms controlling IL-21-mediated cellular responses. IL-21 regulates both innate and adaptive immune responses, and it not only has key roles in antitumour and antiviral responses but also exerts major effects on inflammatory responses that promote the development of autoimmune diseases and inflammatory disorders. Numerous studies have shown that enhancing or inhibiting the action of IL-21 has therapeutic effects in animal models of a wide range of diseases, and various clinical trials are underway. The current challenge is to understand how to specifically modulate the actions of IL-21 in the context of each specific immune response or pathological situation. In this Review, we provide an overview of the basic biology of IL-21 and discuss how this information has been — and can be — exploited therapeutically.

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Figure 1: Sources of IL-21 and its cellular targets.
Figure 2: IL-21 signals through IL-21R and utilizes the JAK–STAT, MAPK and PI3K pathways.
Figure 3: IL-21 has a key role in B cell differentiation and germinal cell development.

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Acknowledgements

This work was supported by the Division of Intramural Research at the National Heart, Lung, and Blood Institute, US National Institutes of Health (NIH). We thank Drs E. E. West and J.-X. Lin for their critical comments.

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  1. Laboratory of Molecular Immunology, National Heart, Lung, and Blood Institute (NHLBI), US National Institutes of Health, Bethesda, 20892, Maryland, USA

    Rosanne Spolski & Warren J. Leonard

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HIV long-term non-progressors

Individuals who have been infected with HIV for long periods of time but can control the infection without the need for antiretroviral therapy. Their viral loads are under 10,000 copies per ml of blood and their CD4+ T cell counts are normal, although they may undergo a slow progression to lower CD4 counts.

Fratricide

The induction of apoptotic death in nearby cells, which normally occurs via a death receptor and its ligand. This occurs naturally in the immune system and other systems, and it can also be induced by chimeric ligands.

Elite controllers

Individuals who are infected with HIV but have extremely low viral loads (<50 copies of RNA per ml). These individuals are believed to have a strong and persistant anti-HIV immune response.

MRL–Faslpr mice

A strain of mice that are deficient for the FAS receptor, which is involved in the induction of cell death. This strain spontaneously develops an autoimmune disease that resembles the human disease systemic lupus erythematosus.

Tape-stripping epicutaneous sensitization

A method for inducing allergic skin inflammation that involves the application of antigen combined with tape stripping, which mimics scratching, leading to skin injury and a heightened allergic response.

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Spolski, R., Leonard, W. Interleukin-21: a double-edged sword with therapeutic potential. Nat Rev Drug Discov 13, 379–395 (2014). https://doi.org/10.1038/nrd4296

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