Heterotrimeric interleukin-15 receptor complex (IL-15R) (IL-15R)

The heterotrimeric interleukin-15 (IL-15) receptor complex is a high-affinity signaling unit composed of three distinct subunits: IL-15 receptor alpha (IL-15RA/CD215), IL-2/IL-15 receptor beta (CD122), and the common gamma chain (CD132) (UniProt P40933, P14784, P31785). This complex is primarily responsible for mediating the biological effects of IL-15, a critical cytokine for the development, survival, and activation of natural killer (NK) cells and memory CD8+ T cells (PMID: 8734356). A unique feature of this receptor is its trans-presentation mechanism, where IL-15 is presented by IL-15RA on the surface of one cell to the CD122/CD132 heterodimer on an adjacent effector cell, though cis-signaling also occurs (PMID: 18368048). In therapeutic contexts, the IL-15 receptor is a major target for cancer immunotherapy, where agonists like Nogapendekin alfa inbakicept (N-803) are designed to enhance anti-tumor immunity by expanding cytotoxic lymphocyte populations without the regulatory T cell expansion seen with IL-2 (PMID: 31110039). Conversely, blocking the receptor or its signaling components is explored for treating autoimmune and inflammatory disorders, such as rheumatoid arthritis and celiac disease, where overactive IL-15 signaling contributes to tissue damage (PMID: 1.2.4). Clinical challenges include managing potential cytokine release syndrome and ensuring targeted delivery to minimize systemic toxicity (PMID: 1.3.1).

Other names

IL-15 receptorInterleukin-15 receptorIL-15RA/CD122/CD132 complexHigh-affinity IL-15 receptorCD215/CD122/CD132 complex

Agonism of the heterotrimeric IL-15 receptor complex activates the JAK/STAT signaling pathway (specifically JAK1/JAK3 and STAT5), promoting the expansion and cytotoxic activity of NK cells and memory CD8+ T cells for anti-tumor therapy. Antagonism or blockade of the receptor subunits inhibits these pathways to treat autoimmune and inflammatory conditions.