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- Title
Mechanistic and structural insight into the functional dichotomy between IL-2 and IL-15.
- Authors
Ring, Aaron M; Lin, Jian-Xin; Feng, Dan; Mitra, Suman; Rickert, Mathias; Bowman, Gregory R; Pande, Vijay S; Li, Peng; Moraga, Ignacio; Spolski, Rosanne; Özkan, Engin; Leonard, Warren J; Garcia, K Christopher
- Abstract
Interleukin 15 (IL-15) and IL-2 have distinct immunological functions even though both signal through the receptor subunit IL-2R? and the common ?-chain (?c). Here we found that in the structure of the IL-15-IL-15R?-IL-2R?-?c quaternary complex, IL-15 binds to IL-2R? and ?c in a heterodimer nearly indistinguishable from that of the IL-2-IL-2R?-IL-2R?-?c complex, despite their different receptor-binding chemistries. IL-15R? substantially increased the affinity of IL-15 for IL-2R?, and this allostery was required for IL-15 trans signaling. Consistent with their identical IL-2R?-?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? versus IL-15R? determined cellular responsiveness. Our results provide new insights for the development of specific immunotherapeutics based on IL-15 or IL-2.
- Subjects
INTERLEUKIN-15; IMMUNOLOGY; CELLULAR signal transduction; MOLECULAR structure; LYMPHOCYTES; CELL differentiation; IMMUNOTHERAPY
- Publication
Nature Immunology, 2012, Vol 13, Issue 12, p1187
- ISSN
1529-2908
- Publication type
Article
- DOI
10.1038/ni.2449