Abstract

Interleukin-1 receptor 8 (IL-1R8, also known as single immunoglobulin IL-1R-related receptor, SIGIRR, or TIR8) is a member of the IL-1 receptor (ILR) family with distinct structural and functional characteristics, acting as a negative regulator of ILR and Toll-like receptor (TLR) downstream signalling pathways and inflammation1. Natural killer (NK) cells are innate lymphoid cells which mediate resistance against pathogens and contribute to the activation and orientation of adaptive immune responses2,3,4. NK cells mediate resistance against haematopoietic neoplasms but are generally considered to play a minor role in solid tumour carcinogenesis5,6,7. Here we report that IL-1R8 serves as a checkpoint for NK cell maturation and effector function. Its genetic blockade unleashes NK-cell-mediated resistance to hepatic carcinogenesis, haematogenous liver and lung metastasis, and cytomegalovirus infection.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Accessions

Primary accessions

Gene Expression Omnibus

References

  1. 1.

    , & The interleukin-1 family: back to the future. Immunity 39, 1003–1018 (2013)

  2. 2.

    Natural killer cell developmental pathways: a question of balance. Annu. Rev. Immunol. 24, 257–286 (2006)

  3. 3.

    et al. Innate or adaptive immunity? The example of natural killer cells. Science 331, 44–49 (2011)

  4. 4.

    et al. Human NK cells and NK receptors. Immunol. Lett. 161, 168–173 (2014)

  5. 5.

    , & Targeting natural killer cells in cancer immunotherapy. Nat. Immunol. 17, 1025–1036 (2016)

  6. 6.

    & Natural killer cells and solid tumors. J. Innate Immun. 3, 355–364 (2011)

  7. 7.

    , , & Effector functions of natural killer cell subsets in the control of hematological malignancies. Front. Immunol. 6, 567 (2015)

  8. 8.

    et al. The receptor SIGIRR suppresses Th17 cell proliferation via inhibition of the interleukin-1 receptor pathway and mTOR kinase activation. Immunity 32, 54–66 (2010)

  9. 9.

    et al. IL-37 requires the receptors IL-18Rα and IL-1R8 (SIGIRR) to carry out its multifaceted anti-inflammatory program upon innate signal transduction. Nat. Immunol. 16, 354–365 (2015)

  10. 10.

    , , & Negative regulatory receptors of the IL-1 family. Semin. Immunol. 25, 408–415 (2013)

  11. 11.

    et al. Human natural killer cells: a unique innate immunoregulatory role for the CD56bright subset. Blood 97, 3146–3151 (2001)

  12. 12.

    et al. Maturation of mouse NK cells is a 4-stage developmental program. Blood 113, 5488–5496 (2009)

  13. 13.

    et al. In vivo developmental stages in murine natural killer cell maturation. Nat. Immunol. 3, 523–528 (2002)

  14. 14.

    et al. Defective NK cell activity and Th1 response in IL-18-deficient mice. Immunity 8, 383–390 (1998)

  15. 15.

    et al. Priming of natural killer cells by nonmucosal mononuclear phagocytes requires instructive signals from commensal microbiota. Immunity 37, 171–186 (2012)

  16. 16.

    et al. Inhibition of Toll-like receptors TLR4 and 7 signaling pathways by SIGIRR: a computational approach. J. Struct. Biol. 169, 323–330 (2010)

  17. 17.

    et al. The metabolic checkpoint kinase mTOR is essential for IL-15 signaling during the development and activation of NK cells. Nat. Immunol. 15, 749–757 (2014)

  18. 18.

    et al. JNK MAP kinase activation is required for MTOC and granule polarization in NKG2D-mediated NK cell cytotoxicity. Proc. Natl Acad. Sci. USA 105, 3017–3022 (2008)

  19. 19.

    & Re-examining the origin and function of liver-resident NK cells. Trends Immunol. 36, 293–299 (2015)

  20. 20.

    et al. Gender disparity in liver cancer due to sex differences in MyD88-dependent IL-6 production. Science 317, 121–124 (2007)

  21. 21.

    et al. The Nlrp3 inflammasome suppresses colorectal cancer metastatic growth in the liver by promoting natural killer cell tumoricidal activity. Immunity 43, 751–763 (2015)

  22. 22.

    , & NK cell interplay with cytomegaloviruses. Curr. Opin. Virol. 15, 9–18 (2015)

  23. 23.

    , , & Innate lymphoid cells: a new paradigm in immunology. Science 348, aaa6566 (2015)

  24. 24.

    et al. Developmental acquisition of regulomes underlies innate lymphoid cell functionality. Cell 165, 1120–1133 (2016)

  25. 25.

    et al. M-CSF induces the expression of a membrane-bound form of IL-18 in a subset of human monocytes differentiating in vitro toward macrophages. Eur. J. Immunol. 42, 1618–1626 (2012)

  26. 26.

    et al. Induced recruitment of NK cells to lymph nodes provides IFN-gamma for T(H)1 priming. Nat. Immunol. 5, 1260–1265 (2004)

  27. 27.

    et al. Increased susceptibility to colitis-associated cancer of mice lacking TIR8, an inhibitory member of the interleukin-1 receptor family. Cancer Res. 67, 6017–6021 (2007)

  28. 28.

    et al. The Toll-interleukin-1 receptor member SIGIRR regulates colonic epithelial homeostasis, inflammation, and tumorigenesis. Immunity 26, 461–475 (2007)

  29. 29.

    & NK cells and cancer: you can teach innate cells new tricks. Nat. Rev. Cancer 16, 7–19 (2016)

  30. 30.

    & NF-κB and STAT3 - key players in liver inflammation and cancer. Cell Res. 21, 159–168 (2011)

  31. 31.

    et al. Intestinal inflammation in mice deficient in Tir8, an inhibitory member of the IL-1 receptor family. Proc. Natl Acad. Sci. USA 101, 3522–3526 (2004)

  32. 32.

    Bbmap: a fast, accurate, splice-aware aligner (Ernest Orlando Lawrence Berkeley National Laboratory, 2014)

  33. 33.

    Cutadapt removes adapter sequences from high-throughput sequencing reads. EMBnet.journal 17, (2011)

  34. 34.

    . et al. STAR: ultrafast universal RNA-seq aligner. Bioinformatics 29, 15–21 (2013)

  35. 35.

    et al. Bioconductor: open software development for computational biology and bioinformatics. Genome Biol. 5, R80 (2004)

  36. 36.

    , & edgeR: a Bioconductor package for differential expression analysis of digital gene expression data. Bioinformatics 26, 139–140 (2010)

  37. 37.

    et al. Opposing roles of polycomb repressive complexes in hematopoietic stem and progenitor cells. Blood 116, 731–739 (2010)

  38. 38.

    et al. limma powers differential expression analyses for RNA-sequencing and microarray studies. Nucleic Acids Res. 43, e47 (2015)

  39. 39.

    et al. Prolonged contact with dendritic cells turns lymph node-resident NK cells into anti-tumor effectors. EMBO Mol. Med. 8, 1039–1051 (2016)

  40. 40.

    , , , & Metastasizing capacity of tumour cells from spontaneous metastases of transplanted murine tumours. Br. J. Cancer 42, 462–472 (1980)

  41. 41.

    , , & Systematic excision of vector sequences from the BAC-cloned herpesvirus genome during virus reconstitution. J. Virol. 73, 7056–7060 (1999)

  42. 42.

    , , , & Efficacious control of cytomegalovirus infection after long-term depletion of CD8+ T lymphocytes. J. Virol. 64, 5457–5464 (1990)

  43. 43.

    et al. Interstitial murine cytomegalovirus pneumonia after irradiation: characterization of cells that limit viral replication during established infection of the lungs. J. Virol. 55, 264–273 (1985)

Download references

Acknowledgements

We thank N. Polentarutti, G. Benigni, M. Erreni, F. Colombo, V. Juranic´ Lisnic´ and D. Kvestak and Computational and Molecular Biology CRUK MI core facilities for technical assistance, M. Nebuloni for hepatocellular carcinoma histology, A. Doni for STED images, and F. Ficara, R. Carriero and D. Mavilio for discussions. The contributions of the European Commission (ERC project PHII-669415; FP7 project 281608 TIMER; ESA/ITN, H2020-MSCA-ITN-2015-676129), Ministero dell’Istruzione, dell’Università e della Ricerca (MIUR) (project FIRB RBAP11H2R9), Associazione Italiana Ricerca sul Cancro (AIRC IG-19014 and AIRC 5x1000-9962), Fondazione CARIPLO (project 2015-0564), European Regional Development Fund (grant KK.01.1.1.01.0006, to S.J.) and the Italian Ministry of Health are gratefully acknowledged. M.M. received a European Federation of Immunological Sciences short-term fellowship to perform viral infection experiments in the laboratory of S.Jo.

Author information

Author notes

    • Eduardo Bonavita

    Present address: Cancer Research UK Manchester Institute, The University of Manchester, Manchester M20 4QL, UK.

    • Martina Molgora
    •  & Eduardo Bonavita

    These authors contributed equally to this work.

Affiliations

  1. Humanitas Clinical and Research Center, 20089 Rozzano, Italy

    • Martina Molgora
    • , Eduardo Bonavita
    • , Andrea Ponzetta
    • , Marialuisa Barbagallo
    • , Sébastien Jaillon
    • , Elena Magrini
    • , Francesca Gianni
    • , Cecilia Garlanda
    •  & Alberto Mantovani
  2. Department of Animal Pathology, Faculty of Veterinary Medicine, University of Milan, 20133 Milan, Italy.

    • Federica Riva
  3. Department of Biomedical Sciences, Humanitas University, 20090 Pieve Emanuele Milan, Italy

    • Sébastien Jaillon
    • , Cecilia Garlanda
    •  & Alberto Mantovani
  4. Faculty of Medicine, University of Rijeka, 51000 Rijeka, Croatia

    • Branka Popović
    •  & Stipan Jonjić
  5. Dipartimento di Medicina Molecolare Istituto Pasteur-Fondazione Cenci Bolognetti, Università di Roma “La Sapienza”, 00161 Rome, Italy

    • Giovanni Bernardini
    •  & Angela Santoni
  6. IRCCS Neuromed, 86077 Pozzilli (IS), Italy

    • Giovanni Bernardini
    •  & Angela Santoni
  7. Cancer Research UK Manchester Institute, The University of Manchester, Manchester M20 4QL, UK

    • Santiago Zelenay
  8. The William Harvey Research Institute, Queen Mary University of London, London EC1M 6BQ, UK.

    • Alberto Mantovani

Authors

  1. Search for Martina Molgora in:

  2. Search for Eduardo Bonavita in:

  3. Search for Andrea Ponzetta in:

  4. Search for Federica Riva in:

  5. Search for Marialuisa Barbagallo in:

  6. Search for Sébastien Jaillon in:

  7. Search for Branka Popović in:

  8. Search for Giovanni Bernardini in:

  9. Search for Elena Magrini in:

  10. Search for Francesca Gianni in:

  11. Search for Santiago Zelenay in:

  12. Search for Stipan Jonjić in:

  13. Search for Angela Santoni in:

  14. Search for Cecilia Garlanda in:

  15. Search for Alberto Mantovani in:

Contributions

E.B. and M.M. played a key role in designing and conducting most experiments and drafted the manuscript. F.R., M.B., F.G. and E.M. provided technological support in in vivo experiments. A.P., S.Ja., B.P. and G.B. contributed to the experimental design and in vivo experiments. S.Z. contributed to RNA-seq analysis. S.Jo. and A.S. contributed to the experimental design and supervision of the study. C.G. and A.M. contributed to the experimental design and supervision of the study, and suggested the role of IL-1R8 as a novel checkpoint inhibitor of NK cells.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Cecilia Garlanda or Alberto Mantovani.

Reviewer Information Nature thanks M. Karin, M. Smyth and the other anonymous reviewer(s) for their contribution to the peer review of this work.

Publisher's note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Extended data

Supplementary information

PDF files

  1. 1.

    Supplementary Figure

    This file shows the murine splenic NK cell gating strategy.

  2. 2.

    Life Sciences Reporting Summary

Excel files

  1. 1.

    Supplementary Table 1

    Gene expression profile of Il1r8+/+ and Il1r8-/-i> NK cells.

About this article

Publication history

Received

Accepted

Published

DOI

https://doi.org/10.1038/nature24293

Further reading

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.