Mechanistic and structural insight into the functional dichotomy between IL-2 and IL-15

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Abstract
The receptors for IL-2 and IL-15 share many characteristics, but mice deficient in either receptor have very different phenotypes. Garcia and colleagues present the quaternary structure of the complex of IL-15 and its receptor, as well as insights into its unique signaling properties. Interleukin 15 (IL-15) and IL-2 have distinct immunological functions even though both signal through the receptor subunit IL-2Rβ and the common γ-chain (γc). Here we found that in the structure of the IL-15–IL-15Rα–IL-2Rβ–γc quaternary complex, IL-15 binds to IL-2Rβ and γc in a heterodimer nearly indistinguishable from that of the IL-2–IL-2Rα–IL-2Rβ–γc complex, despite their different receptor-binding chemistries. IL-15Rα substantially increased the affinity of IL-15 for IL-2Rβ, and this allostery was required for IL-15 trans signaling. Consistent with their identical IL-2Rβ–γc dimer geometries, IL-2 and IL-15 showed similar signaling properties in lymphocytes, with any differences resulting from disparate receptor affinities. Thus, IL-15 and IL-2 induced similar signals, and the cytokine specificity of IL-2Rα versus IL-15Rα determined cellular responsiveness. Our results provide new insights for the development of specific immunotherapeutics based on IL-15 or IL-2.