IL-15 Signaling Pathways and their Primary Biological Effects in Different Immune Cell Types

Interleukin-15 (IL-15) is a four alpha-helix bundle cytokine that is structurally and functionally related to IL-2. It is produced primarily by dendritic cells, monocytes, and epithelial cells. The heterotrimeric IL-15 receptor complex consists of a unique IL-15 R alpha subunit, IL-2/IL-15 R beta, and the common gamma-chain/IL-2 R gamma subunit. Unlike IL-2, IL-15 binds with high affinity to IL-15 R alpha, which then associates with a complex composed of the IL-2/IL-15 R beta and common gamma-chain/IL-2 R gamma subunits, expressed either on the same cell (cis-presentation) or on a different cell (trans-presentation). IL-15 signaling is essential for normal immune system functions. It stimulates T cell proliferation and inhibits IL-2-mediated activation-induced cell death. In addition, IL-15 is required for the development, survival, and activation of natural killer (NK) cells, homeostasis of natural killer T (NKT) cells and intraepithelial lymphocytes, and maintenance of naïve and memory CD8⁺ T cells. Both IL-15- and IL-15 R alpha-deficient mice lack NK cells and have severely reduced numbers of NKT cells, memory CD8⁺ T cells, and specific subsets of intestinal intraepithelial lymphocytes.

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