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

Interleukin-15 (IL-15) and IL-2 possess distinct immunological functions despite both signaling through IL-2Rβ and the common cytokine receptor γ-chain, γ(c), We find that in the IL-15—IL-15Rα—IL-2Rβ—γ(c) quaternary complex structure, IL-15 heterodimerizes IL-2Rβ and γ(c) identically to the IL-2—IL-2Rα—IL-2Rβ—γ(c) complex, despite differing receptor-binding chemistries. IL-15Rα dramatically increases the affinity of IL-15 for IL-2Rβ, and this allostery is required for IL-15 trans-signaling versus IL-2 cis-signaling. Consistent with the identical IL-2Rβ—γ(c) dimer geometry, IL-2 and IL-15 exhibited similar signaling properties in lymphocytes, with any differences resulting from disparate receptor affinities. Thus, IL-15 and IL-2 induce similar signals, and the cytokine-specificity of IL-2Rα versus IL-15Rα determines cellular responsiveness. These results provide important new insights for specific development of IL-15-versus IL-2-based immunotherapeutics.