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-2Rß and the common cytokine receptor ?-chain, ?c, We find that in the IL-15/IL-15Ra/IL-2Rß/?c quaternary complex structure, IL-15 heterodimerizes IL-2Rß and ?c identically to the IL-2/IL-2Ra/IL-2Rß/?c complex, despite differing receptor-binding chemistries. IL-15Ra dramatically increases the affinity of IL-15 for IL-2Rß, and this allostery is required for IL-15 trans-signaling versus IL-2 cis-signaling. Consistent with the identical IL-2Rß/?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-2Ra versus IL-15Ra determines cellular responsiveness. These results provide important new insights for specific development of IL-15- versus IL-2-based immunotherapeutics. Overall design: RNA-Seq is conducted in mouse CD8+ T cells, not treated or treated with IL2 or IL15 for indicated concentrations (1nM or 500nM) and times (4hr or 24hr).

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Ring AM, Lin JX, Feng D, Mitra S, Rickert M, Bowman GR, Pande VS, Li P, Moraga I, Spolski R, Ozkan E, Leonard WJ, Garcia KC