Abstract
Type 1 conventional dendritic (cDC1) cells are necessary for cross-presentation of many viral and tumor antigens to CD8+ T cells. cDC1 cells can be identified in mice and humans by high expression of DNGR-1 (also known as CLEC9A), a receptor that binds dead-cell debris and facilitates XP of corpse-associated antigens. Here, we show that DNGR-1 is a dedicated XP receptor that signals upon ligand engagement to promote phagosomal rupture. This allows escape of phagosomal contents into the cytosol, where they access the endogenous major histocompatibility complex class I antigen processing pathway. The activity of DNGR-1 maps to its signaling domain, which activates SYK and NADPH oxidase to cause phagosomal damage even when spliced into a heterologous receptor and expressed in heterologous cells. Our data reveal the existence of innate immune receptors that couple ligand binding to endocytic vesicle damage to permit MHC class I antigen presentation of exogenous antigens and to regulate adaptive immunity.
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Data availability
Source data are provided with this paper. All other data supporting the findings can be requested from the corresponding author.
Change history
02 February 2021
A Correction to this paper has been published: https://doi.org/10.1038/s41590-021-00885-6.
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Acknowledgements
We thank members of the Immunobiology Laboratory for helpful discussions and suggestions. We thank the Crick BRF and Flow Cytometry STPs for their support throughout this project. We are grateful to P. Faull and B. Snijders for helpful comments. This work was supported by the Francis Crick Institute, which receives core funding from Cancer Research UK (FC001136), the UK Medical Research Council (FC001136) and the Wellcome Trust (FC001136), by an ERC Advanced Investigator grant (AdG 268670), by a Wellcome Investigator Award (WT106973MA) and by a prize from the Louis-Jeantet Foundation. C.M.H. was supported by a FEBS Long-Term Fellowship and a Marie Skłodowska-Curie Individual Fellowship under Horizon 2020 from the European Union. M.D.B. was supported by an EMBO LTF (ALTF 1096-2018) and a Marie Skłodowska-Curie Individual Fellowship under Horizon 2020 from the European Union. F.R. is supported by the MRC (U105170648) and the Wellcome Trust (WT104752MA).
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Contributions
J.C., C.M.H. and H.B. performed most of the experiments. O.S. and H.R. helped with the sorting of single bead MuTuDCs. C.M.H. and M.D.B. performed in vivo experiments. O.S. performed initial experiments and provided key reagents. E.C. helped with confocal experiments. N.C.R. helped with mouse breeding and genotyping. H.R. helped with ImageStream analysis. S.Z. generated the DNGR-1::Dectin-1 chimeras. L.C. and M.C.D. performed electron microscopy. A.A. and S.A. provided advice and training for the PhagoFACS experiments. V.P. provided the Cybb−/− mouse strain. D.C.T. provided reagents that contributed to this study. C.J.E. and F.R. provided the lysenin and galectin probes. H.B., J.C., C.M.H. and C.R.S. interpreted the data and wrote the manuscript. C.R.S. designed and supervised the study.
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Extended data
Extended Data Fig. 1 Bead uptake, CD4+ T cell stimulation and DNGR-1 mediated XP by the cytosolic pathway.
a, OVA and FM-OVA beads stained with anti-ovalbumin, anti-actin or phalloidin analysed by flow cytometry. b, WT MuTuDCs were pulsed with OVA or FM-OVA beads, fixed, stained with anti-OVA to mark uninternalized beads (‘out. beads’) and imaged by confocal microscopy (scale bar 5 µm). Image representative of one experiment. c, FM-OVA bead internalisation by WT, KO and KO-WT MuTuDCs analysed by flow cytometry. MFI from one of two experiments (n = 2). d–e, WT, KO and KO-WT MuTuDCs pulsed with OVA or FM-OVA beads for 4 hrs were co-cultured with OT-I cells. IFN-γ was assessed by ELISA. One of three experiments is shown. Plotted as mean (±s.d.) of experimental duplicates. P values determined using two-way ANOVA. f, ImageStream analysis of WT MuTuDCs pulsed with yellow-green FM-OVA or OVA beads for 4 hrs and sorted for single bead+ MuTuDCs. g, Single bead+ WT MuTuDCs were co-cultured with OT-II cells. CD69+CD4+ T cell frequency was determined by flow cytometry. One of three experiments is shown (n = 3). h–n, WT MuTuDCs were incubated with FM-OVA beads (blue, 10:1, beads:DCs), UV-irradiated bm1 OVA MEFs (red, 3:1, dead cells:DCs) or hen egg white (grey, 1 mg/ml) in the presence of 250 μM leupeptin, 250 μM pepstatin, 10 μM lactacystin, 20 μM lactacystin, 50 μM chloroquine or 500 μM E64. After 4 hrs, OT-I cells were added overnight. OT-I cells alone were also incubated with SIINFEKL peptide (black, 1 nM) in the presence of the inhibitors. IFN-γ was assessed by ELISA, plotted as mean (±s.d.) of experimental duplicates and representative of two independent experiments (n = 2). P values determined using an unpaired t test. n.s., not significant; *P ≤ 0.05; **P ≤ 0.01; ****P ≤ 0.00001.
Extended Data Fig. 2 DNGR-1+ non-degradative phagosome in RAW264.7 macrophages ectopically expressing DNGR-1.
a–g, WT and KO MuTuDCs (a–e), KID (f) or RAW264.7 (g) cells were pulsed with FM-OVA beads for the indicated times. Phagosomes were isolated and stained with anti-DNGR-1, anti-LAMP-2, anti-OVA and anti-MHC I antibodies. Analysis was performed by flow cytometry. Data represented as mean (± s.d.) and from one of two experiments are shown (n = 2). h, Confocal microscopy image of RAW264.7 cells transiently expressing H-2Kb were pulsed with IgG-beads for 2 hrs (scale bar = 6 μm). Each dot represents a single image out of 10 images per condition (n = 10). Data from one representative experiment of two independent experiments (n = 2).
Extended Data Fig. 3 Recruitment of galectin-8 to DNGR-1+ phagosomes containing FM-OVA beads, phagocytosis by cells expressing chimeric receptors and sulforhodimine B release from phagosomes.
a, PhagoFACS of phagosomes isolated from WT MuTuDCs pulsed with FM-OVA beads for 4 hrs and stained with anti-DNGR-1, anti-LAMP-2 and anti-galectin-8 antibodies. Frequency of phagosomes is plotted as mean (± s.d.) for three independent experiments (n = 3). P values were determined by unpaired t test, Welch’s test. b, WT MuTuDCs expressing mCherry::galectin-3 were incubated with OVA or FM-OVA beads (5:1, beads to DCs) for 4 hrs. Cells were fixed, uninternalised beads (‘out. bead’) marked by anti-OVA staining and cells were imaged by confocal microscopy (scale bar = 5 μm). Images are a representative image from 18 FM-OVA and 36 OVA images. c, HEK293T cells expressing cytosolic GFP and C7, C9::C7 or C9(Y7F)::C7 receptors and stained for Dectin-1. Images show a single representative image from 3 similar images. d, HEK293T cells expressing the indicated receptors were pulsed with biotinylated zymosan for 1 hr before fixation and labelling of uninternalised zymosan with fluorescent streptavidin. Internalised zymosan particles were enumerated from replicate confocal images (n = 3 images for empty vector and C7 tail-less, 15 images for C7, C9::C7 and C9(Y7F)::C7 and 5 images for C7 R406 and C9::C7 R406). P values were determined using an unpaired t test. e, HEK293T cells expressing the indicated receptors were challenged with zymosan pre-soaked in sulforhodamine B (SRB). SRB in the cytosol was quantified and normalized to phagosomal fluorescence. Data and images are representative of three independent repeats (n = 3) and n = 40 cells for C9::C7 and 28 cells for C9(Y7F)::C7. Data (d,e) represented as mean (± s.e.m.). P values were determined using an unpaired t test, Welch’s test. n.s., not significant; **P ≤ 0.01; ***P ≤ 0.001.
Extended Data Fig. 4 Generation of HEK293T cell lines able to present OVA on H-2Kb.
a, Confocal microscope images of HEK293T cells stably expressing cytosolic GFP, H-2Kb and either C7, C9::C7 or C9(Y7F)::C7 receptors (anti-Dectin-1 staining). Nuclei were stained with DAPI. Images are representative of 3 similar images (scale bars 5 μm). b, As for (a) but using flow cytometry c, IL-2 from B3Z hybridoma cells cultured with the above H-2Kb-expressing HEK293T cells in the presence of the indicated concentrations of SIINFEKL peptide. Data are plotted as mean (± s.d.) of experimental triplicates from one of three independent experiments (n = 3). P values were determined by two-way ANOVA. d, Confocal images of HEK293T cells stably transfected with empty vector or plasmid encoding either C7, C9::C7 or C9(Y7F)::C7 receptors and pulsed with biotinylated zymosan for 1 hr before fixation and labelling of uninternalised zymosan with fluorescent streptavidin (scale bars 10 μm).. The number of internalised zymosan particles (right) was enumerated from the images (left). Data represented as mean (± s.e.m.) and each dot represents an independent experiment. e, RAW264.7 cells expressing H-2Kb and either C9::C7 or C9(Y7F)::C7 receptors were pulsed with zymosan-OVA for 4 hrs before fixation with 0.5 % PFA and incubated with OT-I cells. IFN-γ was assessed by ELISA. f, LLOMe (1 mM) was added during zymosan-OVA pulse of RAW264.7 cells expressing H-2Kb and C9(Y7F)::C7 receptor. All data in (e,f) are plotted as mean (± s.e.m.) of experimental triplicates. n.s., not significant; **P ≤ 0.01; ****P ≤ 0.00001.
Extended Data Fig. 5 SYK is required for GFP influx into phagosomes.
a, Western blot and confocal microscope images of SYK protein expression in HEK293T SYK KO cells, complemented with mouse mCherry::SYK or mCherry::SYK K396R kinase dead (KD). Bottom panel: mCherry expression of the same micrographs depicted as in Fig. 5c lower panel (scale bar 2 μm). b, Flow cytometry plots measuring phagocytosis of HEK293T WT and SYK KO cells incubated with zymosan-pHrodo-Red particles over 30 min timecourse. Data are representative of two independent experiments (n = 2).
Extended Data Fig. 6 DNGR signalling promotes phagosomal ROS production.
a–b, Confocal images of RAW264.7 cells transfected with empty vector or plasmid encoding C9::C7 or C9(Y7F)::C7 receptors and pulsed with zymosan (a) or dead sRBCs (b) in the presence of Nitroblue tetrazolium (NBT) (Scale bar 10 μm). Quantification of ROS+ phagosomes. Data represented as mean (± s.e.m.) (a) or (± s.d.) (b) and are representative of two independent determinations (n = 2). P values determined by one-way ANOVA. c, RAW264.7 stably expressing C9 or C9(Y7F) receptors were pulsed with CellTracker DeepRed (CTDR)-labelled FP-sRBCs for 2 hrs. Percentage of CTDR+ RAW264.7 cells was quantified by flow cytometry. Data represented as mean (± s.d.) and are representative of two independent experiments (n = 2). d, Confocal images of RAW264.7 stably expressing C9 or C9(Y7F) receptors pulsed with dead cells in the presence of NBT for 2 hrs (scale bars 10 μm). Image is a representative image of three similar images. e, RT-PCR of NADPH oxidase subunits in HEK293T. Representative of two experiments (n = 2). f, HEK293T cells stably expressing C9::C7 were challenged with zymosan-Oxyburst in the presence or absence of DPI for 1 hr. Oxyburst+ positive phagosomes were quantified across 5 fields of view (n > 100 phagosomes). Data represented as mean (± s.e.m.). P values were calculated by unpaired parametric test, Mann-Whitney and are representative of two independent experiments (n = 2). g, HEK293T C9::C7 cells were pulsed with zymosan-Ova (left) or transfected with plasmid encoding VENUS-SIINFEKL (right) in the presence or absence of DPI (10 μM) for 4 hrs before fixing and adding of OT-I Rag1-/- T-cells. IFN-γ was assessed by ELISA, plotted as mean (± s.d.) of an experimental triplicate. n.s., not significant; *P ≤ 0.05; **P ≤ 0.01.
Extended Data Fig. 7 Generation of DNGR-1 and NOX2-deficient cDC1 chimeras.
a, Flow cytometry gating strategy to define and quantify chimeric T cell populations in blood. b, Quantification of percentage chimerism in the blood 8 weeks post adoptive transfer across the indicated genotypes. Each dot is an individual mouse sample (Batf3-/-: Batf3-/- n = 7, Batf3-/-: WT n = 8, Batf3-/-: Clec9acre/cre n = 8, Batf3-/-: Cybb-/- n = 9).
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Supplementary Video 1
SBF SEM 3D reconstruction of damaged phagosome. HEK293T cells expressing mCherry::lysenin and the C9::C7 receptor were incubated with zymosan for 4 h. The 3D reconstruction of a lysenin+ phagosome was carried out as described in the Methods, and the video was prepared using the IMARIS software.
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Canton, J., Blees, H., Henry, C.M. et al. The receptor DNGR-1 signals for phagosomal rupture to promote cross-presentation of dead-cell-associated antigens. Nat Immunol 22, 140–153 (2021). https://doi.org/10.1038/s41590-020-00824-x
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DOI: https://doi.org/10.1038/s41590-020-00824-x
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