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

Nature Immunology volume 13, pages 1187–1195 (2012)Cite this article

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

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Figure 1: The crystal structure of the quaternary IL-15 receptor complex.
Figure 2: Comparison of the site I interfaces of IL-15 and IL-2.
Figure 3: Comparison of the site II interfaces of IL-15 and IL-2.
Figure 4: Enhancement of IL-15–IL-2Rβ interaction by IL-15Rα.
Figure 5: Analysis of signaling by IL-2 and IL-15 in YT-1 human NK cells.
Figure 6: Analysis of signaling by IL-2 and IL-15 in primary mouse CD8+ cells.
Figure 7: RNA-sequencing analysis of gene transcription regulated by IL-2 and IL-15.
Figure 8: Confirmation of differences in the regulation of IL-2 and IL-15 target genes.

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Acknowledgements

We thank E. Long, M. Rubinstein and members of the Leonard and Garcia laboratories for advice and discussions; and N. Goriatcheva, D. Waghray and S. Fischer for technical assistance. Supported by the US National Institutes of Health (R01 AI51321 to K.C.G.; R01 GM062868 to V.S.P.; and National Research Service Award NIH-F30DK094541 to A.M.R.), the American Recovery and Reinvestment Act of 2009 (Public Law 111-5; MRI-R2 to V.S.P.), the Division of Intramural Research of the National Heart, Lung and Blood Institute (US National Institutes of Health; W.J.L., J.-X.L., P.L., S.M. and R.S.), the Stanford Medical Scientist Training Program (NIH-GM07365 to A.M.R.) and the Howard Hughes Medical Institute (K.C.G.).

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Authors and Affiliations

  1. Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, California, USA

    Aaron M Ring, Dan Feng, Mathias Rickert, Ignacio Moraga, Engin Özkan & K Christopher Garcia

  2. Department of Molecular and Cellular Physiology, and Department of Structural Biology, Stanford University School of Medicine, Stanford, California, USA

    Aaron M Ring, Dan Feng, Mathias Rickert, Ignacio Moraga, Engin Özkan & K Christopher Garcia

  3. Laboratory of Molecular Immunology, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland, USA

    Jian-Xin Lin, Suman Mitra, Peng Li, Rosanne Spolski & Warren J Leonard

  4. Department of Chemistry, Stanford University, Stanford, California, USA

    Gregory R Bowman & Vijay S Pande

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Contributions

A.M.R., D.F. and E.Ö. did crystallographic studies of the IL-15 quaternary complex; A.M.R. and E.Ö. determined and refined that structure; M.R. did SPR measurements; G.R.B. and V.S.P. did and analyzed molecular dynamics simulations; A.M.R. prepared cytokine proteins for signaling and transcriptional studies; A.M.R., S.M., I.M. and R.S. did signaling experiments by flow cytometry with phosphorylation-specific antibodies; A.M.R. did receptor-internalization studies; J.-X.L. and P.L. did and analyzed RNA sequencing transcriptional assays; J.-X.L. confirmed the quantitative PCR; A.M.R., J.-X.L., G.R.B., W.J.L. and K.C.G. designed the experiments; A.M.R., J.-X.L., P.L., S.M. and G.R.B. prepared the figures; A.M.R., W.J.L. and K.C.G. wrote the paper; and W.J.L. and K.C.G. supervised the research.

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Correspondence to K Christopher Garcia.

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Competing interests

K.C.G. has filed a patent (US 2011/066911) describing the IL-2 'superkine' H9.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–4 and Tables 1–2 (PDF 1343 kb)

Supplementary Spreadsheet 1

Genes more potently regulated by IL-2. (XLS 188 kb)

Supplementary Spreadsheet 2

Genes more potently regulated by IL-15. (XLS 203 kb)

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Ring, A., Lin, JX., Feng, D. et al. Mechanistic and structural insight into the functional dichotomy between IL-2 and IL-15. Nat Immunol 13, 1187–1195 (2012). https://doi.org/10.1038/ni.2449

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