Interleukin-2 receptor subunit beta and Interleukin-2 receptor subunit gamma complex (IL-2Rβγ)

The Interleukin-2 receptor subunit beta (CD122) and Interleukin-2 receptor subunit gamma (CD132) complex is a heterodimeric receptor that mediates the signaling of Interleukin-2 (IL-2) in effector immune cells, such as memory CD8+ T cells and natural killer (NK) cells (UniProt P14784, P31785). This intermediate-affinity receptor complex is distinct from the high-affinity heterotrimeric receptor that includes the alpha subunit (CD25), which is predominantly expressed on regulatory T cells (Tregs) and vascular endothelial cells (PubMed: 22391954). Binding of IL-2 to the βγ complex activates the JAK1/JAK3 and STAT5 signaling pathways, driving the expansion and cytolytic activity of CD8+ T cells, which are essential for anti-tumor immunity (PubMed: 29628290). In modern drug development, this complex is targeted by engineered IL-2 variants, often called not-alpha or biased IL-2, which are designed to selectively bind the βγ subunits while avoiding CD25. This strategy aims to maximize the activation of tumor-killing cells while minimizing the expansion of immunosuppressive Tregs and reducing the risk of vascular leak syndrome, a common side effect of wild-type IL-2 therapy (Nature Reviews Immunology: 10.1038/s41577-022-00770-6).

Other names

CD122/CD132 complexIntermediate-affinity interleukin-2 receptorIL-2Rβ/γ heterodimerIL-2R beta-gamma complex

Selective agonism of the intermediate-affinity IL-2 receptor complex (IL-2Rβγ) to promote the expansion of effector CD8+ T cells and natural killer (NK) cells while minimizing the activation of regulatory T cells (Tregs) and reducing binding to the high-affinity IL-2Rα subunit.