| IL-2Rβ (CD122/p75) is the signaling-competent β chain of the type I cytokine receptor family that partners with the common γ chain (γc/CD132) and, in the high‑affinity complex, IL-2Rα (CD25) to form the functional IL‑2 receptor, where it provides the critical intracellular platform that couples IL‑2 binding to JAK–STAT, PI3K–AKT–mTOR and MAPK/ERK pathway activation in T cells and NK cells. The extracellular region of IL‑2Rβ contributes one of the three binding interfaces that clamp IL‑2 in the high‑affinity quaternary signaling complex, while the transmembrane segment anchors the receptor and the cytoplasmic tail carries defined motifs that bind and activate JAK1 and serve as substrates and docking sites for STAT5, Shc, and PI3K once phosphorylated. IL‑2 engagement first involves rapid capture by IL‑2Rα on activated T cells, followed by recruitment of constitutively expressed IL‑2Rβ and γc to form the trimeric receptor; heterodimerization of the IL‑2Rβ and γc cytoplasmic domains activates JAK1 and JAK3, which phosphorylate multiple tyrosines within the IL‑2Rβ tail and generate binding sites for STAT5, Shc, and the p85 PI3K regulatory subunit, thereby initiating three coordinated signaling cascades. STAT5 recruitment and phosphorylation dominate IL‑2Rβ‑dependent transcriptional output in most T‑cell subsets, with STAT5 dimers driving expression of genes that promote clonal expansion, survival, and effector differentiation, including CD25, PRDM1/BLIMP‑1, and a range of cytokines and cell‑cycle regulators. In parallel, PI3K binding to IL‑2Rβ leads to PIP3 generation, PDK1/AKT recruitment, and activation of AKT–mTOR signaling, which supports glucose uptake, biosynthetic metabolism, and expression of factors such as BCL‑6, while Shc recruitment couples IL‑2Rβ to RAS–RAF–MEK–ERK signaling and induction of cyclins that drive cell‑cycle progression. The same IL‑2Rβ–STAT5 axis underpins the development and maintenance of regulatory T cells, but with distinct quantitative and contextual features: Tregs rely heavily on sustained STAT5 signaling downstream of IL‑2Rβ/γc for FOXP3 expression and survival, while showing minimal use of PI3K–AKT, a divergence that contributes to different functional outcomes of IL‑2Rβ engagement in Tregs versus effector T cells despite shared receptor components. IL‑2Rβ also participates in intermediate‑affinity IL‑2 receptor complexes (β/γc dimers) on memory T cells and NK cells, where IL‑2Rβ–JAK1–STAT5 signaling promotes cytotoxicity, IFN‑γ production, and homeostatic proliferation, and these β/γc‑biased configurations are being exploited by engineered IL‑2 muteins that preferentially stimulate effector or regulatory populations in cancer and autoimmune disease. |
