Interleukin-15 receptor subunit beta and common subunit gamma complex (IL-15Rβγ) (IL-15Rβγ)

The Interleukin-15 receptor subunit beta and common subunit gamma complex (IL-15Rβγ) is a heterodimeric cytokine receptor primarily expressed on natural killer (NK) cells and memory CD8+ T cells (Waldmann, 2006, Nature Reviews Immunology). It consists of the IL-15 receptor subunit beta (CD122) and the common subunit gamma (CD132), which together form an intermediate-affinity binding site for the cytokine IL-15 (UniProt P14784, P31785). While IL-15 can also bind to a high-affinity trimeric receptor containing IL-15Rα, the βγ complex is the critical signaling component that triggers the JAK/STAT pathway, specifically activating JAK1, JAK3, and STAT5 (Robinson & Schluns, 2017, Journal of Leukocyte Biology). In the context of cancer immunotherapy, this complex is a major therapeutic target because its stimulation promotes the proliferation and cytotoxic activity of NK and CD8+ T cells, which are essential for anti-tumor immunity. Unlike IL-2, which shares the βγ subunits but also strongly activates regulatory T cells (Tregs) via the IL-2Rα (CD25) subunit, IL-15-based therapies can be designed to selectively expand effector cells over suppressive ones. Several drugs, including IL-15 superagonists and fusion proteins like nogapendekin alfa inbakicept, are being developed or have been approved to leverage this pathway for treating various malignancies (FDA, 2024, N-803 Approval). However, clinical use requires careful management of safety concerns such as cytokine release syndrome and potential off-target immune activation.

Other names

CD122/CD132 complexIL-15Rβ/γcIntermediate-affinity IL-15 receptorIL-15 receptor beta-gamma complexInterleukin-2/15 receptor subunit beta and common gamma chain complex

Agonism of the IL-15Rβγ complex to activate the JAK/STAT signaling pathway, specifically JAK1/JAK3 and STAT5, leading to the expansion and activation of NK cells and CD8+ T cells.