Interleukin 23 (IL-23) regulates the development of TH17 cells, which are important for antimicrobial and antifungal responses and autoimmune and chronic inflammatory diseases. IL-23-induced Jak/STAT signaling is mediated via the heterodimeric IL-23 receptor (IL-23R)-IL-12 receptor 1 (IL-12R1) complex. The typical signal-transducing receptor of the IL-6/IL-12 family contains three extracellularmembrane-proximal fibronectin type III (FNIII) domains, which are not involved in cytokine binding but are mandatory for signal transduction. In place of FNIII-type domains, IL-23R has a structurally undefined stalk. We hypothesized that the IL-23R stalk acts as a spacer to position the cytokine binding domains at a defined distance from the plasma membrane to enable signal transduction. Minor deletions of the murine, but not of the human, IL-23R stalk resulted in unresponsiveness to IL-23. Complete deletion of the human IL-23R stalk and the extended murine IL-23R stalk, including a 20-amino-acid-long duplication of domain 3, however, induced ligandindependent, autonomous receptor activation, as determined by STAT3 phosphorylation and cell proliferation. Ligand-independent, autonomous activity was caused by IL-23R homodimers and was independent of IL-12R1. Our data show that deletion of the stalk results in biologically active IL-23R homodimers, thereby creating an asyet-undescribed receptor complex of the IL-6/IL-12 cytokine family.KEYWORDS IL-23 receptor, IL-23 signaling T he proinflammatory cytokine interleukin 23 (IL-23) is a member of the IL-6/IL-12 family (1). IL-23 regulates the development of TH17 cells, which are important mediators of antimicrobial and antifungal responses. Furthermore, they are involved in the pathogenesis of autoimmune and chronic inflammatory diseases (2). IL-23 binding initiates the heterodimerization of the  receptor chains IL-23 receptor (IL-23R) and IL-12R1. Subsequently, receptor-associated tyrosine kinase 2 (Tyk2) and Janus kinase 2 (Jak2) activate independent signaling pathways, including the Jak/STAT, the mitogenactivated protein kinase (MAPK)/Erk, and the phosphatidylinositol 3-kinase (PI3K)/Akt pathways. IL-23 predominantly activates STAT3 and to a lesser extent STAT1, STAT4, and STAT5 (3, 4).IL-12R1 was considered a ligand binding receptor (5). However, it was demonstrated that IL-12R1 is important for kinase binding and activation. Moreover, association of Jak2 with IL-23R is mandatory for IL-23 signaling, whereas Tyk2 seems to be dispensable (6).IL-23R is composed of an N-terminal immunoglobulin-like domain 1 (D1) and a cytokine binding module (CBM) formed by domains 2 and 3 (D2 and D3), which carry
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