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 mouse IL-15 shares 70% and 96% amino acid sequence identity with human and rat IL-15, respectively. IL-15 binds with high affinity to IL?15 R alpha (3). 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 (4). IL-15 associates with IL-15 R alpha in the endoplasmic reticulum, and this complex is expressed on the cell surface (5). 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 (6). This enables cells to respond to IL-15 even if they do not express IL-15 R alpha (5). 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 in circulation (7-9). Soluble IL-15 R alpha functions as an inhibitor that limits IL-15 action (3, 8). 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 (10). IL-15 induces or enhances the differentiation, maintenance, or activation of multiple T cell subsets including NK, NKT, Th17, Treg, and CD8+ memory cells (11-15). An important component of these functions is the ability of IL-15 to induce dendritic cell differentiation and inflammatory activation (10, 13). IL-15 exhibits anti-tumor activity independent of its actions on NK cells or CD8+ T cells (16). It also inhibits the deposition of lipid in adipocytes, and its circulating levels are decreased in obesity (17).
