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.

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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., 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.


  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


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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.

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    Supplementary Figure

    This file shows the murine splenic NK cell gating strategy.

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    Life Sciences Reporting Summary

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    Supplementary Table 1

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

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