IL-15 receptor, i.e. IL-15 receptor complex, specifically binding IL-15 with high affinity, consists of an interleukin 15 receptor alpha subunit, IL-2 receptor beta and gamma subunits. Interleukin 15 (IL-15) has a key role in promoting survival, proliferation and activation of natural killer (NK) and CD8+ T cells. Despite its functional similarities to IL-2, IL-15 affects a wider range of target cell populations and utilizes different mechanisms of signaling.
We will mainly discuss IL-15 receptor (IL-15R) alpha, IL-15 receptor (IL-15R) signaling and targeting IL-15/IL-15 receptor system in the following.
Only the IL-15 receptor alpha (IL-15RA) subunit is unique to IL-15. IL-15 receptor alpha is expressed by mitogen-activated macrophages, NK cells, and CD4+ and CD8+ T cells. Comparison of the IL-2 receptor alpha (IL-2Rα) and the IL-15 receptor alpha (IL-15Rα) revealed the presence of a conserved protein binding motif (sushi domain or GP-1 motif) and similar intron/exon structure, placing IL-2Rα and IL-15Rα as the founding members of a new receptor family.
IL-15 receptor alpha is located on mouse chromosome 2 and human chromosome 10p. The human IL-15RA consists of seven exons, and alternative mRNA splicing may result in eight molecular IL-15Rα isoforms with different extra- or intracellular domains. Full-length isoforms consist of an extracellular portion containing the Sushi (i.e. IL-15-binding) domain, a trans-membrane domain, and an intracellular tail. Human IL-15 receptor alpha shares 45% amino acid (aa) homology with the mouse form of the receptor.
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IL-15 receptor alpha initiates signaling of IL-15. IL-15 supports cell expansion and maintenance by (i) inducing strong proliferative signals via JAK/STAT and Ras/MAPK signaling pathways and (ii) preventing cell death by increasing antiapoptotic proteins Bcl-2 and Bcl-Xl, as well as decreasing proapoptotic proteins Bim and Puma through activation of the PI3K pathway.
IL-15 signaling is also well known to evoke a Th1 immune response by inducing release of IFNγ and TNFα. IL-15 can also trigger a Th2 response through release of IL-4 and IL-5 in activated human T cells.
Disordered IL-15 expression has been reported in patients with an array of inflammatory autoimmune diseases. A series of therapeutic agents that inhibit IL-15 action have been introduced, including the soluble IL-15 receptor (IL-15R) alpha subunit, mutant IL-15, and antibodies directed against the IL-15 cytokine and against the IL-2R/IL-15R β subunit used by IL-2 and IL-15.
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