Intermediate-affinity interleukin-2 receptor (IL-2Rbeta/gamma)

The intermediate-affinity interleukin-2 receptor (IL-2Rbeta/gamma) is a signaling complex composed of the interleukin-2 receptor subunit beta (IL2RB/CD122) and the common cytokine receptor gamma chain (IL2RG/CD132) (Liao et al., 2013, Immunity). Unlike the high-affinity trimeric receptor that includes the alpha subunit (CD25), the beta/gamma heterodimer is constitutively expressed on the surface of natural killer (NK) cells and resting memory CD8+ T cells (Waldmann, 2006, Nat Rev Immunol). Binding of interleukin-2 (IL-2) to this receptor triggers the JAK/STAT signaling pathway, specifically activating JAK1 and JAK3 to phosphorylate STAT5, which promotes the proliferation and cytolytic activity of effector immune cells (Spolski et al., 2018, Nat Rev Immunol). In oncology, this receptor is a primary target for biased IL-2 agonists designed to selectively stimulate anti-tumor CD8+ T and NK cells while avoiding the activation of CD25-expressing regulatory T cells (Tregs), which otherwise suppress the immune response (Bentebibel et al., 2019, Cancer Discovery). Therapeutic development focuses on maximizing the activation of this intermediate-affinity complex to enhance immunotherapy efficacy while minimizing systemic toxicities such as vascular leak syndrome and pulmonary edema associated with high-affinity receptor binding on vascular endothelium.

Other names

CD122/CD132 complexInterleukin-2 receptor subunit beta/gamma heterodimerDimeric IL-2 receptorIL-2RβγIL-2 receptor beta-gamma

Selective agonism of the IL-2Rbeta/gamma complex to stimulate the expansion and activation of CD8+ effector T cells and Natural Killer (NK) cells, while avoiding the activation of CD25-positive regulatory T cells (Tregs) and vascular endothelial cells (Liao et al., 2013, Immunity; Bentebibel et al., 2019, Cancer Discovery).