Medium-affinity interleukin-2 receptor (IL-2Rβγ)

The medium-affinity interleukin-2 receptor (IL-2R) is a heterodimeric signaling complex composed of the IL-2Rβ (CD122) and IL-2Rγ (CD132) subunits (UniProt: P14784, P31785). It is distinct from the high-affinity trimeric receptor, which includes the IL-2Rα (CD25) subunit, and the low-affinity monomeric CD25 receptor (PubMed: 22391154). The medium-affinity complex is constitutively expressed on resting T cells and natural killer (NK) cells, serving as a critical mediator of immune cell activation and proliferation through the JAK/STAT signaling pathway (StatPearls: Interleukin-2). In the context of drug development, this receptor is the primary target for "CD25-independent" or "not-alpha" IL-2 variants, such as Nemvaleukin alfa (PubMed: 31040119). These therapeutic agents are engineered to bypass CD25-expressing regulatory T cells (Tregs), which can inhibit anti-tumor immunity, and instead preferentially activate effector CD8+ T cells and NK cells to enhance the body's ability to eliminate cancer cells. While targeting this receptor aims to reduce the severe toxicities like vascular leak syndrome associated with high-affinity IL-2R binding, managing systemic immune activation remains a key clinical challenge (PubMed: 34161864).

Other names

CD122/CD132 complexInterleukin-2 receptor beta/gamma heterodimerIL-2Rβ/γIL-2R subunit beta/gamma

Agonism of the IL-2Rβγ complex to activate the JAK/STAT signaling pathway, specifically promoting the expansion of effector CD8+ T cells and NK cells.