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Interleukin-21 Signaling: Functions in Cancer and Autoimmunity

Authors' Affiliations: ¹ Ludwig-Austin Joint Medical Oncology Unit, Austin Health; ² Peter MacCallum Cancer Centre, Melbourne, Australia; ³ Novo Nordisk A/S, Copenhagen, Denmark; and ⁴ ZymoGenetics, Seattle, Washington

Requests for reprints: Ian D. Davis, Ludwig-Austin Joint Medical Oncology Unit, Austin Hospital, Studley Road, Heidelberg, Victoria 3084, Australia. Phone: 61-3-9496-5726; Fax: 61-3-9457-6698; E-mail: Ian.Davis{at}ludwig.edu.au.

Abstract

Interleukin-21 (IL-21) is a cytokine with structural and sequence homology to IL-2 and IL-15, yet possesses several biological properties distinct from these cytokines. IL-21 is produced mainly by activated CD4⁺ T cells and natural killer T cells and mediates its activity by binding to the IL-21 receptor (IL-21R), consisting of an IL-21–specific chain (IL-21R; JAK/STAT) that heterodimerizes with the common chain (CD132). Intracellular signaling occurs through the Janus-activated kinase/signal transducer and activator of transcription pathways. Physiologic expression of IL-21R is restricted to lymphoid tissues and peripheral blood mononuclear cells; however, other tissues such as epithelium, synovium, or transformed cells can acquire expression of both components of IL-21R heterodimer. IL-21 has complex activities on a wide variety of cell types, leading to enhancement of adaptive T-cell immunity, antibody production, activation of natural killer cell subtypes, and opposition to suppressive effects mediated by regulatory T cells. Functionally, these activities promote immune responses and point to a physiologic role of IL-21 in autoimmunity and immune enhancement. Therapeutic manipulation of IL-21 activity may allow improved immunotherapy for cancer as well as insights into autoimmune disease. Recently conducted phase 1 trials in metastatic melanoma and renal cell carcinoma have shown that recombinant IL-21 has a favorable safety profile and support its continued investigation as a potential anticancer drug.