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

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 (T H 17) 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. The cytokine interleukin-21 (IL-21) regulates immune responses and has potential therapeutic relevance in diseases including cancer, viral infections, autoimmune diseases and allergies. Spolski and Leonard describe our current understanding of IL-21 biology, and discuss progress in harnessing this knowledge therapeutically, including clinical trials of IL-21 itself and molecules that block IL-21 signalling. 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 — expl