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

Interleukin 15 (IL-15) and IL-2 have distinct immunological functions even though both signal through the receptor subunit IL-2R beta and the common gamma-chain (gamma(c)). Here we found that in the structure of the IL-15-IL-15R alpha-IL-2R beta-gamma(c) quaternary complex, IL-15 binds to IL-2R beta and gamma(c) in a heterodimer nearly indistinguishable from that of the IL-2-IL-2R alpha-IL-2R beta-gamma(c) complex, despite their different receptor-binding chemistries. IL-15R alpha substantially increased the affinity of IL-15 for IL-2R beta, and this allostery was required for IL-15 trans signaling. Consistent with their identical IL-2R beta-gamma(c) 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-2R alpha versus IL-15R alpha determined cellular responsiveness. Our results provide new insights for the development of specific immunotherapeutics based on IL-15 or IL-2.