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

Aaron M. Ring, Jian Xin Lin, Dan Feng, Suman Mitra, Mathias Rickert, Gregory R. Bowman, Vijay S. Pande, Peng Li, Ignacio Moraga, Rosanne Spolski, Engin Özkan, Warren J. Leonard, K. Christopher Garcia

Research output: Contribution to journalArticlepeer-review

143 Scopus citations

Abstract

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 (γ c). Here we found that in the structure of the IL-15-IL-15Rα-IL-2Rβ-γ c quaternary complex, IL-15 binds to IL-2Rβ and γ c in a heterodimer nearly indistinguishable from that of the IL-2-IL-2Rα-IL-2Rβ-γ c 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-γ 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-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.

Original languageEnglish
Pages (from-to)1187-1195
Number of pages9
JournalNature immunology
Volume13
Issue number12
DOIs
StatePublished - Dec 2012

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