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.
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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.
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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.
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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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Extended data figures and tables
Extended Data Figure 1 Expression of IL-1R8 in human and mouse NK cells.
a, b, IL1R8 mRNA expression in human primary NK cells, compared with T and B cells, neutrophils, monocytes and in vitro-derived macrophages (a) and in human primary NK cell maturation stages (CD56brCD16−, CD56brCD16+, CD56dimCD16+), and in the CD56dimCD16− subset (b). c, Representative FACS plot of human NK cell subsets and histograms of IL-1R8 expression in NK cell subsets. d, IL-1R8 protein expression in human bone marrow precursors and mature cells. e, ILR family member (Il1r1, Il1r2, Il1r3, Il1r4, Il1r5, Il1r6, Il1r8) mRNA expression in mouse primary NK cells isolated from the spleen. f, IL-1R8 protein expression in mouse NK cells by confocal microscopy. Scale bars, 10 μm. g, Representative FACS plot of mouse NK cell subsets. a, b, d, *P < 0.05, **P < 0.01, ***P < 0.001. One-way ANOVA. Mean ± s.e.m. a, n = 6 (NK and B cells) or n = 4 donors; b, n = 5 donors; d, n = 4 donors; e, n = 2 mice; f, representative images out of four collected per group. a, b, d–f, One experiment performed.
Extended Data Figure 2 Phenotypic analysis of Il1r8−/− NK cells.
a, b, Representative plot of fluorescence-activated cell sorting of mouse NK cell subsets in Il1r8+/+ and Il1r8−/− mice (a) and histograms of KLRG1 expression in NK cells (b). c, d, NK absolute number and NK cell subsets (DN, CD11blow, DP and CD27low) in bone marrow, spleen and blood of Il1r8+/+ and Il1r8−/− newborn mice at 2 (c) and 3 (d) weeks of age. e, Frequency of bone marrow precursors in Il1r8+/+ and Il1r8−/− mice. f, NKG2D, DNAM-1 and LY49H expression in peripheral NK cells and NK cell subsets of Il1r8+/+ and Il1r8−/− mice. g, Frequency of splenic Perforin+ NK cell subsets upon stimulation in Il1r8+/+ and Il1r8−/− mice. h, i, Peripheral NK cell absolute number (h) and CD27low NK cell frequency (i) in bone marrow chimaeric mice upon reconstitution (9 weeks). j, k, Peripheral NK cell (j) and NK cell subset (k) frequency in competitive chimaeric mice transplanted with 50% of Il1r8+/+ CD45.1 cells and 50% of Il1r8−/− CD45.2 cells upon reconstitution (9 weeks). Upon reconstitution, a defective engraftment (12% instead of 50% engraftment) of Il1r8−/− stem cells was observed in competitive conditions. l, IFNγ production by Il1r8+/+ and Il1r8−/− NK cells upon co-culture with LPS- or CpG-primed Il1r8+/+ and Il1r8−/− dendritic cells. c–l, *P < 0.05, **P < 0.01, ***P < 0.001 between selected relevant comparisons, two-tailed unpaired Student’s t-test. Centre values and error bars, mean ± s.e.m. At least five animals per group were used. c, d, Three pooled experiments; e–l, one experiment was performed.
Extended Data Figure 3 Mechanism of IL-1R8-dependent regulation of NK cells.
a, Splenic CD27low NK cell frequency in wild-type, Il1r8−/−, Il18−/− and Il18−/−/Il1r8−/− mice. b, Peripheral CD27low NK cell frequency in wild-type, Il1r8−/−, Il1r1−/− and Il1r8−/−Il1r1−/− mice (left) and IFNγ production by splenic NK cells after IL-12 and IL-1β or IL-18 stimulation (right). c, d, Splenic CD27low NK cell frequency in Il1r8+/+ and Il1r8−/− mice upon commensal flora depletion (c) and breeding in co-housing conditions (d). e, STED microscopy of human NK cells stimulated with IL-18. Magnification bar, 2 μm. a–d, *P < 0.05, **P < 0.01, ***P < 0.001 between selected relevant comparisons, two-tailed unpaired Student’s t-test; Centre values and error bars, mean ± s.e.m. a, n = 3, 5, or 6 mice; at least five animals per group were used (b–d). a–d, One experiment was performed. e, Representative images out of three collected from two donors.
Extended Data Figure 4 RNA-seq analysis of Il1r8+/+ and Il1r8−/− NK cells.
Metascape analysis of enriched gene pathways of resting and IL-18-activated Il1r8+/+ and Il1r8−/− NK cells. See also Supplementary Table 1 and data deposited in the NCBI Gene Expression Omnibus under accession number GSE105043.
Extended Data Figure 5 NK-cell-mediated resistance to hepatocellular carcinoma and metastasis in IL-1R8-deficient mice.
a, Macroscopic score of liver lesions in female Il1r8+/+ and Il1r8−/− mice 6, 10 and 12 months after diethylnitrosamine (DEN) injection. b, Incidence of hepatocellular carcinoma in Il1r8+/+ and Il1r8−/− female and male mice. c, Frequency of IFNγ+ NK cells in spleen of Il1r8+/+ and Il1r8−/− tumour-bearing mice. d, Macroscopic score of liver lesions in female Il1r8+/+ and Il1r8−/− mice upon NK cell depletion. e, 2-Deoxyglucosone (2-DG) quantification in lungs of Il1r8+/+ and Il1r8−/− tumour-bearing mice upon NK cell depletion. f, Primary tumour growth in Il1r8+/+ and Il1r8−/− mice (25 days after MN/MCA1 cell line injection). g, Number of lung metastases in Il1r8+/+ and Il1r8−/− MN/MCA1 sarcoma-bearing mice upon IFNγ or IL-18 neutralization. h, Volume of lung metastases in Il1r8+/+ and Il1r8−/− MN/MCA1-bearing mice upon depletion of IL-17A or CD4+/CD8+ cells. i, Number of lung metastases in Il1r8+/+ and Il1r8−/−, Il1r1−/−, Il1r1−/−/Il1r8−/− MN/MCA1-bearing mice. j, Number of liver metastases in Il1r8+/+, Il1r8−/−, Il18−/−, Il18−/−Il1r8−/− MC38 colon carcinoma-bearing mice. k, Il1r8+/+ and Il1r8−/− NK cell absolute number 3 or 7 days after adoptive transfer. l, In vivo Il1r8+/+ and Il1r8−/− NK cell proliferation 3 days after adoptive transfer. m, Ex vivo IFNγ production and degranulation upon 4 h stimulation with PMA-ionomycin, IL-12 and IL-18 in adoptively transferred Il1r8+/+ and Il1r8−/− NK cells. n, Volume of lung metastases in Il1r8+/+ MN/MCA1 sarcoma-bearing mice after adoptive transfer of Il1r8+/+ and Il1r8−/− NK cells. a, c–e, g–j, m–n, *P < 0.05, **P < 0.01, ***P < 0.001 between selected relevant comparisons, two-tailed unpaired Student’s t-test or Mann–Whitney U-test. #P < 0.05, ##P < 0.01, Kruskal–Wallis and Dunn’s multiple comparison test. Centre values and error bars, mean ± s.e.m. a, n = 9, 10, 11, 18, 21 mice; b, n = 8–21 mice; c, n = 6 mice; d, n = 10, 12, 13 mice; e, n = 4 (Il1r8−/− isotype) or n = 5; f, n = 10; g, n = 6, 7, 9, 10 mice; h, n = 5, 6, 12 mice; i, n = 6, 8, 10 mice; j, n = 4, 5, 7 mice; k, l, m, n = 3 mice; n, n = 9, 10, 12 mice. Representative experiment out of three (a, b), 2 (d), 6 (f), or one (c, e, g–n) experiments performed. NT, not treated.
Extended Data Figure 6 NK-cell-mediated anti-viral resistance in IL-1R8-deficient mice.
Cytokine serum levels in Il1r8+/+ and Il1r8−/− infected mice (1.5 and 4.5 days after infection). *P < 0.05, **P < 0.01, ***P < 0.001, unpaired Student’s t-test. Centre values and error bars, mean ± s.e.m.; n = 5 mice. One experiment was performed.
Supplementary information
Supplementary Figure
This file shows the murine splenic NK cell gating strategy.
Supplementary Table 1
Gene expression profile of Il1r8+/+ and Il1r8-/-i> NK cells.
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Molgora, M., Bonavita, E., Ponzetta, A. et al. IL-1R8 is a checkpoint in NK cells regulating anti-tumour and anti-viral activity. Nature 551, 110–114 (2017). https://doi.org/10.1038/nature24293
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DOI: https://doi.org/10.1038/nature24293
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