Interleukin-2 receptor, intermediate-affinity form (IL-2Rβγ)

The intermediate-affinity interleukin-2 receptor (IL-2R) is a dimeric protein complex consisting of the IL-2Rβ (CD122) and IL-2Rγ (CD132) subunits (UniProt P14784, P31785). It is primarily expressed on natural killer (NK) cells and resting memory CD8+ T cells, where it mediates the proliferative and activating effects of IL-2 through the JAK/STAT signaling pathway (StatPearls, Interleukin-2). Unlike the high-affinity trimeric receptor (αβγ), which includes the CD25 subunit and is constitutively expressed on regulatory T cells (Tregs), the intermediate-affinity form has a lower binding affinity for native IL-2. This difference in affinity and cellular distribution makes the βγ complex a critical target for next-generation cancer immunotherapies. Biased IL-2 agonists, such as Bempegaldesleukin or NL-201, are engineered to preferentially bind the intermediate-affinity receptor to stimulate anti-tumor effector cells while avoiding the activation of immunosuppressive Tregs (Nature, 2019). Consequently, this receptor form is central to strategies aimed at enhancing the therapeutic index of cytokine-based treatments by reducing systemic toxicities like vascular leak syndrome while maintaining potent anti-tumor activity.

Other names

IL-2 receptor beta/gamma complexCD122/CD132 complexIntermediate-affinity IL-2 receptorIL-2RbgInterleukin-2 receptor subunit beta/gamma

Agonism of the IL-2Rβ (CD122) and IL-2Rγ (CD132) subunits to trigger the JAK/STAT signaling pathway, specifically activating JAK1, JAK3, and STAT5 to promote the expansion and activation of effector immune cells.