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Identification of a dendritic cell receptor that couples sensing of necrosis to immunity

Nature volume 458, pages 899–903 (2009)Cite this article

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Abstract

Injury or impaired clearance of apoptotic cells leads to the pathological accumulation of necrotic corpses, which induce an inflammatory response that initiates tissue repair1. In addition, antigens present in necrotic cells can sometimes provoke a specific immune response2,3,4 and it has been argued that necrosis could explain adaptive immunity in seemingly infection-free situations, such as after allograft transplantation or in spontaneous and therapy-induced tumour rejection5,6. In the mouse, the CD8α+ subset of dendritic cells phagocytoses dead cell remnants and cross-primes CD8+ T cells against cell-associated antigens7. Here we show that CD8α+ dendritic cells use CLEC9A (also known as DNGR-1), a recently-characterized C-type lectin8,9,10, to recognize a preformed signal that is exposed on necrotic cells. Loss or blockade of CLEC9A does not impair the uptake of necrotic cell material by CD8α+ dendritic cells, but specifically reduces cross-presentation of dead-cell-associated antigens in vitro and decreases the immunogenicity of necrotic cells in vivo. The function of CLEC9A requires a key tyrosine residue in its intracellular tail that allows the recruitment and activation of the tyrosine kinase SYK, which is also essential for cross-presentation of dead-cell-associated antigens. Thus, CLEC9A functions as a SYK-coupled C-type lectin receptor to mediate sensing of necrosis by the principal dendritic-cell subset involved in regulating cross-priming to cell-associated antigens.

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Figure 1: Ligand(s) for CLEC9A are exposed after cell death.
Figure 2: CLEC9A is required for cross-presentation of dead-cell-associated antigens in vitro.
Figure 3: CLEC9A signalling is necessary for efficient cross-presentation of dead-cell-associated antigens.
Figure 4: CLEC9A is necessary for cross-priming to dead-cell-associated antigens in vivo.

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Change history

  • 16 April 2009

    A magnification value in Fig. 2 legend was corrected on 16 April 2009.

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Acknowledgements

This work was funded by Cancer Research UK. D.S. was supported by an EMBO long-term fellowship (ALTF 336-2004) and by a Marie Curie Intra-European Fellowship within the sixth European Community Framework Programme (MEIF-CT-2005-009205). We thank E. Schweighoffer and V. Tybulewicz for fetal liver from Syk-/- embryos. We also thank N. Shastri for B3Z and BWZ cell lines and A. Eddaoudi for assistance with cell sorting. We are grateful to members of the Immunobiology Laboratory, Cancer Research UK, for advice and discussions and the Biological Resources staff for animal care and assistance with mouse experiments.

Author Contributions D.S. and O.P.J. performed most of the experiments. A.M.K. performed the phospho-SYK staining and analysis of CLEC9A subcellular distribution. D.S., O.P.J. and C.R.S. planned the research, analysed and interpreted data and wrote the manuscript. N.C.R. helped with mouse breeding and genotyping. D.M. performed and analysed cell sorting and multispectral flow cytometry experiments. P.H.-F. generated SYK transfectants. I.R. contributed to the generation of CLEC9A-deficient mice.

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Author notes

  1. David Sancho and Olivier P. Joffre: These authors contributed equally to this work.

Authors and Affiliations

  1. Immunobiology Laboratory,,

    David Sancho, Olivier P. Joffre, Anna M. Keller, Neil C. Rogers, Patricia Hernanz-Falcón & Caetano Reis e Sousa

  2. FACS Laboratory, Cancer Research UK, London Research Institute, Lincoln’s Inn Fields Laboratories, 44 Lincoln’s Inn Fields, London WC2A 3PX, UK ,

    Dolores Martínez

  3. Trangenic Services, Cancer Research UK, Clare Hall Laboratories, Blanche Lane, South Mimms, Potters Bar, Hertfordshire EN6 3LD, UK ,

    Ian Rosewell

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Sancho, D., Joffre, O., Keller, A. et al. Identification of a dendritic cell receptor that couples sensing of necrosis to immunity. Nature 458, 899–903 (2009). https://doi.org/10.1038/nature07750

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