Interleukin-2 receptor (IL-2R) signaling axis (IL-2/IL-2R axis)

The Interleukin-2 (IL-2) receptor signaling axis is a fundamental pathway in the adaptive immune system, primarily responsible for the growth, survival, and differentiation of T-lymphocytes and natural killer (NK) cells (UniProt P01585). The functional receptor exists in three forms: a low-affinity monomer (CD25), an intermediate-affinity dimer (CD122 and CD132), and a high-affinity trimer (CD25, CD122, and CD132) (PubMed: 22391954). Upon IL-2 binding, the receptor triggers the JAK/STAT, PI3K/Akt, and MAPK/ERK signaling cascades, which are essential for maintaining immune homeostasis and self-tolerance through the support of regulatory T-cells (Tregs) (PubMed: 29103952). In clinical practice, this axis is targeted in two opposing ways: high-dose IL-2 agonists like Aldesleukin are used to boost anti-tumor immunity in metastatic melanoma and renal cell carcinoma, while IL-2R antagonists like Basiliximab are used to prevent acute organ rejection (StatPearls: NBK513257). Recent therapeutic developments focus on biased IL-2 molecules designed to selectively activate either effector cells for cancer or Tregs for autoimmune conditions, aiming to reduce the severe side effects associated with systemic IL-2 administration, such as vascular leak syndrome (PubMed: 33854234). This axis also serves as a target for immunotoxins like Denileukin diftitox, which delivers cytotoxic payloads to CD25-expressing malignant cells in cutaneous T-cell lymphoma (PubMed: 11713467). Monitoring the axis often involves measuring soluble IL-2 receptor levels or STAT5 phosphorylation to assess pathway activation and patient response (PubMed: 25639280).

Other names

IL-2 signaling pathwayT-cell growth factor receptor complexCD25/CD122/CD132 signaling axisIL2/IL2R axis

Agonism of the high-affinity IL-2 receptor complex to promote lymphocyte expansion for cancer immunotherapy; selective agonism of the trimeric receptor to expand regulatory T-cells in autoimmunity; antagonism of the IL-2R alpha subunit to inhibit T-cell mediated graft rejection.