IL-15Rα membrane-anchorage either in cis or in trans is required for stabilization of IL-15 and optimal signaling

Interleukin(IL)-15 plays an important role in the communication between immune cells. IL-15 delivers its signal through different modes involving three receptor chains: IL-15Rα, IL-2Rβ and γc. The combination of the different chains result in the formation of IL-15Rα/IL-2Rβ/γc trimeric or IL-2Rβ/γc dimeric receptors. In this study, we aimed at investigating the role of IL-15Rα chain in stabilizing the cytokine in the IL-2Rβ/γc dimeric receptor. By analyzing the key residues of IL-15 facing IL-2Rβ, we provided evidence of differential interfaces in the presence or in the absence of membrane-anchored IL-15Rα. Moreover, we found that the anchorage of IL-15Rα to the cell surface regardless its mode of presentation, in cis or in trans, is crucial for complete signaling. These observations show how the cells can finely modulate the intensity of cytokine signaling through the quality and the level of expression of the receptor chains.