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

被引:562
作者
Sancho, David [1 ,2 ]
Joffre, Olivier P. [1 ,2 ]
Keller, Anna M. [1 ,2 ]
Rogers, Neil C. [1 ,2 ]
Martinez, Dolores [3 ]
Hernanz-Falcon, Patricia [1 ,2 ]
Rosewell, Ian [3 ]
Reis e Sousa, Caetano [1 ,2 ]
机构
[1] Lincolns Inn Fields Labs, Immunobiol Lab, London WC2A 3PX, England
[2] Lincolns Inn Fields Labs, London Res Inst, Canc Res UK, FACS Lab, London WC2A 3PX, England
[3] Imperial Canc Res Fund, Clare Hall Labs, Canc Res UK, Trangen Serv, Potters Bar EN6 3LD, Herts, England
关键词
ACTIVATION; ADJUVANTS; DANGER; CLEC9A; DEATH;
D O I
10.1038/nature07750
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
Injury or impaired clearance of apoptotic cells leads to the pathological accumulation of necrotic corpses, which induce an inflammatory response that initiates tissue repair(1). In addition, antigens present in necrotic cells can sometimes provoke a specific immune response(2-4) 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 rejection(5,6). In the mouse, the CD8 alpha(+) subset of dendritic cells phagocytoses dead cell remnants and cross-primes CD8(+) T cells against cell-associated antigens(7). Here we show that CD8 alpha(+) dendritic cells use CLEC9A (also known as DNGR-1), a recently-characterized C-type lectin(8-10), 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 CD8 alpha(+) 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.
引用
收藏
页码:899 / 903
页数:5
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