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

2009; Nature Portfolio; Volume: 458; Issue: 7240 Linguagem: Inglês

10.1038/nature07750

1476-4687

David Sancho, Olivier Joffre, Anna M. Keller, Neil C. Rogers, Dolores Martínez, Patricia Hernanz‐Falcón, Ian Rosewell, Caetano Reis e Sousa,

T-cell and B-cell Immunology

Necrotic cell corpses accumulate in tissues as a result of injury or impaired clearance of apoptotic cells, and can induce an inflammatory response that initiates tissue repair. The recently described dendritic C-type lectin receptor CLEC9A, also called DNGR-1, is shown to sense necrotic debris by recognizing a preformed signal that is exposed on necrotic cells, and to mediate cross presentation of dead cell-associated antigens. This study shows that dendritic cells use the C-type lectin CLEC9A to sense necrotic cell debris and to mediate cross-presentation of dead-cell-associated antigens. 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.