The multifaceted regulation of interleukin-15 expression and the role of this cytokine in NK cell differentiation and host response to intracellular pathogens

Interleukin-15 (IL-15) is a 14- to 15-kDa member of the 4 alpha-helix bundl e family of cytokines. IL-15 expression is controlled at the levels of tran scription, translation, and intracellular trafficking. In particular, IL-15 protein is posttranscriptionally regulated by multiple controlling element s that impede translation, including 12 upstream AUGs of the 5' UTR, 2 unus ual signal peptides, and the C-terminus of the mature protein. IL-15 uses t wo distinct receptor and signaling pathways. In T and NK cells the IL-15 re ceptor includes IL-2/15R beta and gamma(c) subunits, which are shared with IL-2, and an IL-15-specific receptor subunit, IL-15R alpha. Mast cells resp ond to IL-15 with a receptor system that does not share elements with the I L-2 receptor but uses a novel 60- to 65-kDa IL-15RX subunit. In mast cells IL-15 signaling involves Jak2/STAT5 activation rather than the Jak1/Jak3 an d STAT5/STAT3 system used in activated T cells. In addition to its other fu nctional activities in immune and nonimmune cells, IL-15 plays a pivotal ro le in the development, survival, and function of NK cells. Abnormalities of IL-15 expression have been described in patients with rheumatoid arthritis or inflammatory bowel disease and in diseases associated with the retrovir uses HIV and HTLV-I. New approaches directed toward IL-15, its receptor, or its signaling pathway may be of value in the therapy of these disorders.