IL-15 is a 14-15 kDa glycoprotein encoded by a 34 kb region on chromosome 4q31. The human IL-15 gene consists of 9 exons and 8 introns, with 4 exons (exon 5 to exon 8) encoding the mature protein.
The heterotrimeric IL-15 receptor is composed of a b subunit shared with the IL-2 receptor (IL-2R/IL-15Rb), a common g subunit shared with IL-2, IL-4, IL-7, IL-9, and IL-21 (gc), and a unique subunit (IL-15Ra) conferring specificity to the IL-15 receptor. IL-15Ra is widely expressed in humans and mice, independently of IL-2R/IL-15Rb-gc. It binds IL-15 with high affinity (Kd>10-11M) and retains IL-15 on the cell surface. IL-15Ra trans-presents IL-15 by forming an immune synapse with adjacent effector NK cells and T cells expressing IL-2R/IL-15Rb-gc. This immune synapse mechanism is thought to limit exposure to circulating IL-15, restrict excessive immune stimulation, and reduce the risk of uncontrolled autoimmune responses due to IL-15 exposure.
IL-15 was initially identified for its ability to stimulate T cells. It signals through the common IL-2-like cell proliferation receptor components (IL-2R/IL-15Rb-gc) and activates signaling pathways involving JAK1/JAK3 and STAT3/STAT5. Similar to IL-2, IL-15 has been shown to stimulate proliferation, activation of CD4-CD8-, CD4+CD8+, CD4+ and CD8+ T cells, promote induction of cytotoxic T lymphocytes, and support the production, proliferation, and activation of NK cells.
