Interleukin-15 receptor heterotrimeric 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-15Rα (CD215), IL-2/IL-15Rβ (CD122), and the common gamma chain (γc, CD132) [Waldmann, 2013]. This complex is predominantly expressed on Natural Killer (NK) cells and memory CD8+ T cells, where it plays a pivotal role in their development, homeostasis, and activation [Mishra et al., 2014]. A unique aspect of IL-15 biology is its "trans-presentation," where IL-15Rα on the surface of dendritic cells or macrophages presents the cytokine to the βγ subunits on responding lymphocytes [Robinson & Schluns, 2017]. Signaling through this complex primarily activates the JAK1/JAK3 and STAT5 pathways, promoting cell survival and proliferation without the significant regulatory T cell (Treg) expansion typically seen with IL-2 [Waldmann, 2013]. In oncology, the IL-15 receptor is a major target for agonists like nogapendekin alfa inbakicept, which are designed to enhance anti-tumor immunity by expanding effector cell populations [FDA, 2024]. Conversely, blocking the receptor or its subunits is explored as a strategy for treating autoimmune and inflammatory disorders, such as celiac disease, where IL-15 drives pathogenic lymphocyte activity [Mishra et al., 2014].

Other names

IL-15Rαβγ complexHigh-affinity IL-15 receptorCD215/CD122/CD132 complexIL-15 receptor subunit alpha/beta/gamma

Agonism of the high-affinity receptor complex to stimulate the expansion and cytotoxic activity of NK and CD8+ T cells; Antagonism of receptor subunits to inhibit IL-15-mediated inflammatory signaling.