National Center for
4GS7: Structure of the Interleukin-15 Quaternary Complex
Nat. Immunol. (2012) 13 p.1187-1195
Interleukin 15 (IL-15) and IL-2 have distinct immunological functions even though both signal through the receptor subunit IL-2Rbeta and the common gamma-chain (gamma(c)). Here we found that in the structure of the IL-15-IL-15Ralpha-IL-2Rbeta-gamma(c) quaternary complex, IL-15 binds to IL-2Rbeta and gamma(c) in a heterodimer nearly indistinguishable from that of the IL-2-IL-2Ralpha-IL-2Rbeta-gamma(c) complex, despite their different receptor-binding chemistries. IL-15Ralpha substantially increased the affinity of IL-15 for IL-2Rbeta, and this allostery was required for IL-15 trans signaling. Consistent with their identical IL-2Rbeta-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-2Ralpha versus IL-15Ralpha determined cellular responsiveness. Our results provide new insights for the development of specific immunotherapeutics based on IL-15 or IL-2.