Interleukin 15 (IL-15) is a widely expressed 14?kDa cytokine that is structurally and functionally related to IL-2 and plays an important role in many immunological diseases (1, 2). Mature human IL-15 protein shares 70% amino acid sequence identity with mouse and rat IL-15. Alternative splicing generates isoforms of Interleukin 15 with either a long or short signal peptide (LSP or SSP), and the SSP isoform is retained intracellularly (3). The IL-15 protein binds with high affinity to IL-15 R alpha (4). It binds with lower affinity to a complex of IL-2 R beta and the common gamma chain?( gamma c) which are also subunits of the IL-2 receptor complex (5). IL-15 associates with IL-15 R alpha in the endoplasmic reticulum, and this complex is expressed on the cell surface (6). The dominant mechanism of IL-15 action is known as transpresentation in which IL-15 and IL-15 R alpha are coordinately expressed on the surface of one cell and interact with complexes of IL-2 R beta / gamma c on adjacent cells (7). This enables cells to respond to Interleukin 15 even if they do not express IL-15 R alpha (6). In human and mouse, soluble IL-15-binding forms of IL-15 R alpha can be generated by proteolytic shedding and bind up nearly all the IL-15 protein in circulation (8-10). Soluble IL-15 R alpha functions as an inhibitor that limits IL-15 action (4,?9). Ligation of membrane-associated IL-15/IL-15 R alpha complexes also induces reverse signaling that promotes activation of the IL-15/IL-15 R alpha expressing cells (11). IL-15 induces or enhances the differentiation, maintenance, or activation of multiple T?cell subsets including NK, NKT, Th17, Treg, and CD8+?memory cells (12 - 16). An important component of these functions is the ability of?IL-15 to induce dendritic cell differentiation and inflammatory activation (11, 14). IL-15 exhibits anti-tumor activity independent of its actions on NK cells or CD8+?T?cells (17). It also inhibits the deposition of lipid in adipocytes, and its circulating levels are decreased in obesity (18).
