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

The Interleukin-2 receptor subunit beta and subunit gamma complex (IL-2Rβγ) is a heterodimeric cytokine receptor composed of the IL-2 receptor subunit beta (CD122) and the common cytokine receptor gamma chain (CD132) (UniProt P14784, P31785). It serves as the intermediate-affinity receptor for Interleukin-2 (IL-2) and is the primary signaling unit responsible for the activation and proliferation of effector immune cells, such as CD8+ cytotoxic T cells and natural killer (NK) cells (Liao et al., 2013, Immunity). Unlike the high-affinity heterotrimeric receptor (αβγ) which includes the CD25 subunit and is constitutively expressed on regulatory T cells (Tregs), the βγ dimer is the predominant signaling form on resting effector lymphocytes (Ross & Cantrell, 2018, Annual Review of Immunology). This makes the IL-2Rβγ complex a critical therapeutic target in oncology, where selective activation aims to enhance anti-tumor immunity while avoiding the immunosuppressive effects of Treg stimulation (Malek, 2008, Annual Review of Immunology).\n\nTherapeutic agents targeting this complex primarily consist of "biased" IL-2 agonists or engineered IL-2 variants designed to selectively bind the βγ subunits and minimize interaction with the α subunit (CD25) (Bentebibel et al., 2019, Cancer Discovery). By avoiding CD25 binding, these drugs seek to mitigate the severe systemic toxicities, such as vascular leak syndrome and pulmonary edema, that are associated with high-dose recombinant IL-2 therapy (Spolski et al., 2018, Nature Reviews Immunology). Several candidates, including nemvaleukin alfa and various pegylated IL-2 prodrugs, have been investigated in clinical trials for the treatment of advanced solid tumors like melanoma and renal cell carcinoma (Silk et al., 2021, Expert Opinion on Investigational Drugs). Monitoring target engagement often involves measuring STAT5 phosphorylation and the expansion of CD8+ T cell populations relative to Tregs (Waldmann, 2018, Cold Spring Harbor Perspectives in Biology).

Other names

CD122/CD132 complexIntermediate-affinity interleukin-2 receptorIL-2 receptor beta/gammaIL-2R beta-gamma

Selective agonism of the IL-2Rβγ complex to activate the JAK/STAT signaling pathway, specifically inducing STAT5 phosphorylation, which leads to the proliferation and activation of CD8+ effector T cells and natural killer (NK) cells while minimizing the activation of CD25-expressing regulatory T cells (Tregs) [3][5][6].