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

By D. Sancho, O. Joffre, Anna M. Keller, N. Rogers, Dolores Martínez, Patricia Hernanz-Falcón, I. Rosewell, C. Reis e Sousa. Nature, 2009

768 citations recorded by the source corpus.

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 CD8α+ subset of dendritic cells phagocytoses dead cell remnants and cross-primes CD8+ T cells against cell-associated antigens. Here we show that CD8α+ 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 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.

Subfields: Immunology

View Paper: https://www.semanticscholar.org/paper/e3b561250aa4c14de437ae12d309937e553e7f4b

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Citations in the corpus

Signalling through C-type lectin receptors: shaping immune responses (2009, background): “Recently, CLeC9A has been shown to be involved in the recognition of dead cell remnants that are phagocytosed by DCs for cross-presentation to CD8 + T cells 78 .”
Cancer immunotherapy via dendritic cells (2012, positive): “Importantly, CLEC9a is also a receptor for necrotic cells, and has been shown to facilitate cross-presentation [74].”
Phagocytosis: An Immunobiologic Process. (2016, background): “and colleagues have defined a novel pathway of phagocytic clearance of dying apoptotic and necrotic cells and their debris via a C-type lectin, CLEC9A (DNGR-1) (Ahrens et al., 2012; Sancho et al., 2009).”
Human CD141+ (BDCA-3)+ dendritic cells (DCs) represent a unique myeloid DC subset that cross-presents necrotic cell antigens (2010, background): “CLEC9A also acts as a sensor of necrotic cells and regulator of cross-priming in mice (Sancho et al., 2009).”
Human Tissues Contain CD141hi Cross-Presenting Dendritic Cells with Functional Homology to Mouse CD103+ Nonlymphoid Dendritic Cells (2012, background): “Other markers such as CLEC9A and XCR1 are highly discriminatory, as emphasized by others (Caminschi et al., 2008; Huysamen et al., 2008; Sancho et al., 2009; Crozat et al., 2011), but are difficult to stain on tissue cells.”
Immunogenic death of colon cancer cells treated with oxaliplatin (2010, background): “tumor-specific cytotoxic T lymphocytes, in a dendritic cell (DC)-dependent manner (Apetoh et al., 2007b; Tesniere et al., 2008; Sancho et al., 2009).”
Activation of the NLRP3 inflammasome in dendritic cells induces IL-1β–dependent adaptive immunity against tumors (2009, background): “However, addition of recombinant calreticulin or HMGB1 to live cancer cells is not sufficient to elicit the presentation of tumor antigens by DC”
The SYK tyrosine kinase: a crucial player in diverse biological functions (2010, background): “CLEC9A is highly expressed by subsets of DCs and monocytes and recognizes as yet unidentified ligands that are exposed during cell necrosi”
Immunogenic and tolerogenic cell death (2009, background): “Dying cells also expose or release another as yet unidentified DAMP that is recognized by the receptor C-type lectin domain family 9, member A (CLEC9A), which is expressed by CD8α + DC”
Quantitative proteomics reveals subset-specific viral recognition in dendritic cells. (2010, background): “Activation of CD8a+ cDCs would increase in an environment of viral-induced cell death because the expression of receptors such as Clec9a (Sancho et al., 2009), equipping CD8a+ cDCs for the uptake of dying cells, allows the subsequent transport of the viral-loaded dead cell cargo to the endosomes…”