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

Abstract

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 within 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 CD8α ⁺ subset of dendritic cells (DC) phagocytoses dead cell remnants and crossprimes CD8 ⁺ T cells against cell-associated antigens 7. Here, we show that CD8α ⁺ DC utilise CLEC9A (DNGR-1), a recently-characterised C-type lectin 8- 10, to recognise a preformed signal that is exposed on necrotic cells. Loss or blockade of CLEC9A does not impair uptake of necrotic cell material by CD8α ⁺ DC but specifically reduces crosspresentation 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 within its intracellular tail that allows recruitment and activation of the tyrosine kinase Syk, which is also essential for crosspresentation of dead cell-associated antigens. Thus, CLEC9A functions as a Syk-coupled C-type lectin receptor to mediate sensing of necrosis by the principal DC subset involved in regulating crosspriming to cell-associated antigens.