1. Immunobiology Laboratory,
2. FACS Laboratory, Cancer Research UK, London Research Institute, Lincoln's Inn Fields Laboratories, 44 Lincoln's Inn Fields, London WC2A 3PX, UK
3. Trangenic Services, Cancer Research UK, Clare Hall Laboratories, Blanche Lane, South Mimms, Potters Bar, Hertfordshire EN6 3LD, UK
4. These authors contributed equally to this work.

Correspondence to: Caetano Reis e Sousa¹ Correspondence and requests for materials should be addressed to C.R.S. (Email: caetano@cancer.org.uk).

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 response^{2, 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 rejection^{5, 6}. In the mouse, the CD8⁺ subset of dendritic cells phagocytoses dead cell remnants and cross-primes CD8⁺ T cells against cell-associated antigens⁷. Here we show that CD8⁺ dendritic cells use CLEC9A (also known as DNGR-1), a recently-characterized C-type lectin^{8, 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 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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