Identification of a dendritic cell receptor that couples sensing of necrosis to immunity
Open accessAbstract
Injury or impaired clearance of apoptotic cells leads to the pathological accumulation of necrotic corpses, which induce an inflammatory response that initiates tissue repair. In addition, antigens present in necrotic cells can sometimes provoke a specific immune response 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 rejection. In the mouse, the CD8alpha+ subset of dendritic cells phagocytoses dead cell remnants and cross-primes CD8+ T cells against cell-associated antigens. Here we show that CD8alpha+ dendritic cells use CLEC9A (also known as DNGR-1), a recently-characterized C-type lectin, 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 CD8+ 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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Caspase activation has multiple effects on the immunogenicity of cell death.
“The activation of caspases, a specific class of cysteine proteases has multiple effects on the immunogenicity of cell death 56”
From Immunogenic and tolerogenic cell death (2009) · cites this paper as [56]
Necrosis has traditionally been considered an accidental, uncontrolled form of cell death occurring only in pathological circumstances.
“Necrosis has traditionally been considered merely as an accidental, uncontrolled form of cell death that only occurs in pathological circumstances.”
From Immunogenic and tolerogenic cell death (2009) · cites this paper as [56]
There are several distinct subtypes of apoptosis that are morphologically similar but triggered through different biochemical routes, such as the intrinsic or extrinsic pathway or with or without caspase activation.
“There are several distinct subtypes of apoptosis that, although morphologically similar, can be triggered through different biochemical routes (for example, through the intrinsic or the extrinsic pathway or with or without caspase activation).”
From Immunogenic and tolerogenic cell death (2009) · cites this paper as [56]
Necrosis is morphologically characterized by cell volume gain (oncosis), organelle swelling, plasma membrane rupture, and loss of intracellular contents.
“Necrosis is morphologically characterized by a gain in cell volume (oncosis), swelling of organelles, plasma membrane rupture and subsequent loss of intracellular contents.”
From Immunogenic and tolerogenic cell death (2009) · cites this paper as [56]
Autophagic cell death occurs without chromatin condensation but with massive autophagic vacuolization of the cytoplasm.
“Autophagic cell death occurs in the absence of chromatin condensation but is accompanied by massive autophagic vacuolization of the cytoplasm.”
From Immunogenic and tolerogenic cell death (2009) · cites this paper as [56]
Apoptosis is accompanied by cell rounding, pseudopod retraction, reduced cell volume (pyknosis), chromatin condensation, nuclear fragmentation (karyorrhexis), few or no ultrastructural changes in cytoplasmic organelles, and plasma membrane blebbing, with cell integrity maintained until the final stages.
“Apoptosis is accompanied by rounding-up of the cell, retraction of pseudopods, reduction of cellular volume (pyknosis), chromatin condensation, nuclear fragmentation (karyorrhexis), few or no ultrastructural modifications of cytoplasmic organelles, and plasma membrane blebbing but cell integrity is maintained until the final stages of the process.”
From Immunogenic and tolerogenic cell death (2009) · cites this paper as [56]
The apparent uniformity of apoptotic cell death may conceal heterogeneous functional aspects, such as whether dying apoptotic cells are recognized by the immune system.
“Furthermore, the apparent uniformity of apoptotic cell death may conceal heterogeneous functional aspects, such as whether or not dying apoptotic cells are recognized by the immune system 56.”
From Immunogenic and tolerogenic cell death (2009) · cites this paper as [56]
CLEC9A has been shown to recognize necrotic cells and induce the cross-presentation of dead cell-associated antigens to CD8+ T cells.
“CLeC9A has been shown to recognize necrotic cells and induce the cross-presentation of dead cell-associated antigens to CD8+ T cells.”
From Sterile inflammation: sensing and reacting to damage (2010) · cites this paper as [75]
CLEC9A may be involved in regulating sterile immune responses, although the specific ligand recognized in this case is still unknown.
“Therefore, it may be involved in regulating sterile immune responses, although the specific ligand recognized in this case is still unknown73,75.”
From Sterile inflammation: sensing and reacting to damage (2010) · cites this paper as [75]
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- Authors
- Sancho, D., Joffre, O. P., Keller, A. M., Rogers, N. C., Martínez, D., Hernanz-Falcón, P., Rosewell, I., & Sousa, C. R. E.
- Affiliations
- The Honourable Society of Lincoln's Inn (GB)
- Cancer Research UK (GB)
- Corresponding author
- Sousa, Caetano Reis e
- Venue
- Nature
- Published
- 2009-04
- Volume
- 458
- Issue
- 7240
- Pages
- 899-903
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC2671489
- OpenAlex
- W2136883776
- Cited by
- 750
- References
- 27
- Citations by year
- 2026: 17 · 2025: 35 · 2024: 31 · 2023: 44 · 2022: 45 · 2021: 39 · 2020: 44 · 2019: 38 · 2018: 37 · 2017: 30 · 2016: 47 · 2015: 49 · 2014: 54 · 2013: 55 · 2012: 61
- FWCI
- 26.41
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- Cancer Research UK (A3598)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Life Sciences › Immunology and Microbiology › Immunology › Phagocytosis and Immune Regulation
- Keywords
- CLEC9A, DNGR-1, C-type lectin receptors, dendritic cells, CD8α+ dendritic cells, necrosis, cross-presentation, Syk, immunogenicity, tissue repair, inflammation, allograft rejection, tumor rejection
- MeSH terms
- Animals, Cells, Cultured, Dendritic Cells, Humans, Ligands, Necrosis, Phagocytosis, Receptors, Immunologic, Receptors, Mitogen, Signal Transduction, CD8 Antigens, CD8-Positive T-Lymphocytes, Lectins, C-Type, Cross-Priming, Mice
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