Interleukin 15: biology and relevance to human disease.

Since the cloning of interleukin (IL)-15 six years ago, there have been numerous studies examining the molecular and cellular biology of this cytokine. IL-15 and IL-2 have similar biologic properties in vitro, consistent with their shared receptor (R) signaling components (IL-2/15Rbgc). However, specificity for IL-15 versus IL-2 is provided by unique private a-chain receptors that complete the IL-15Rabg and IL-2Rabg heterotrimeric high-affinity receptor complexes and thereby allow differential responsiveness depending on the ligand and highaffinity receptor expressed. Intriguingly, both IL-15 and IL15Ra transcripts have a much broader tissue distribution than IL-2/IL-2Ra. Further, multiple complex posttranscriptional regulatory mechanisms tightly control IL-15 expression. Thus, based upon complex regulation, as well as differential patterns of IL-15 and IL-15Ra expression, it is likely that the critical in vivo functions of this receptor/ligand pair differ from those of IL-2 and IL-2Ra. Studies to date examining the biology of IL-15 have identified several key nonredundant roles, such as IL-15’s importance during natural killer (NK) cell, NK–T cell, and intestinal intraepithelial lymphocyte development and function. A role for IL-15 during autoimmune processes such as rheumatoid arthritis and malignancies such as adult T-cell leukemia suggest that dysregulation of IL-15 may result in deleterious effects for the host. This review attempts to present concisely our current understanding of the cellular and molecular biology of IL-15, IL-15’s role in human disease, and its potential clinical utility as a therapeutic agent or target.