| ST2, encoded by the IL1RL1 gene, belongs to the interleukin-1 receptor superfamily and functions as the receptor for the alarmin cytokine IL-33. The gene generates two principal isoforms through alternative splicing: a membrane-bound transmembrane receptor, ST2L, and a truncated soluble form, sST2, that lacks the transmembrane and intracellular signaling domains. ST2L carries an extracellular domain built from three immunoglobulin-like folds, a single transmembrane segment, and a cytoplasmic Toll/IL-1 receptor domain that couples the receptor to the MyD88-dependent signaling cascade shared with other IL-1 family members. Binding of IL-33 to ST2L, together with recruitment of the IL-1 receptor accessory protein, triggers MyD88 and TRAF6 engagement, driving downstream activation of NF-κB and amplifying transcription of type 2 effector cytokines. ST2L is constitutively and abundantly expressed on Th2 and GATA-3-positive regulatory T cells through a GATA-3- and STAT5-dependent transcriptional program, while Th1 and cytotoxic T cells express ST2L only transiently upon activation, under control of T-bet and STAT4. This expression pattern extends beyond T cells to mast cells, type 2 innate lymphoid cells, eosinophils, basophils, NK cells, and non-immune populations including cardiomyocytes and endothelial cells, positioning the IL-33/ST2 axis as a convergence point for both innate and adaptive type 2 immune signaling. sST2 circulates independently of the membrane receptor and sequesters IL-33 before it can engage ST2L, functioning as a decoy that limits productive signaling; common genetic variation at the IL1RL1 locus directly regulates circulating sST2 concentrations and downstream pathway activity. Because IL-33/ST2 signaling shapes Th2 polarization, regulatory T cell maintenance, and mast cell and ILC2 effector function, this pathway is central to allergic and type 2 inflammatory disease, while elevated circulating sST2 is associated with increased cardiovascular disease risk, linking receptor isoform balance to both immunological and cardiac outcomes. |
