The receptor DNGR-1 signals for phagosomal rupture to promote cross-presentation of dead-cell-associated antigens
CORRESPONDENCE TO: caetano@crick.ac.uk
Canton J, Blees H, Henry CM, et al. The receptor DNGR-1 signals for phagosomal rupture to promote cross-presentation of dead-cell-associated antigens. Nat Immunol 2020.
Type 1 conventional dendritic (cDC1) cells are necessary for cross-presentation of many viral and tumor antigens to CD8+T cells. cDC1 cells can be identified in mice and humans by high expression of DNGR-1 (also known as CLEC9A), a receptor that binds dead-cell debris and facilitates XP of corpse-associated antigens. Here, we show that DNGR-1 is a dedicated XP receptor that signals upon ligand engagement to promote phagosomal rupture. This allows escape of phagosomal contents into the cytosol, where they access the endogenous major histocompatibility complex class I antigen processing pathway. The activity of DNGR-1 maps to its signaling domain, which activates SYK and NADPH oxidase to cause phagosomal damage even when spliced into a heterologous receptor and expressed in heterologous cells. Our data reveal the existence of innate immune receptors that couple ligand binding to endocytic vesicle damage to permit MHC class I antigen presentation of exogenous antigens and to regulate adaptive immunity .
I型常規樹突狀細胞（cDC1）對於很多病毒及腫瘤抗原交叉呈遞給CD8+T細胞至關重要。cDC1細胞可以通過DNGR-1（又名CLEC9A）的高表達在人類和小鼠中識別，DNGR-1是一種結合死細胞碎片並促進相關抗原XP的受體。在這裡，我們發現了DNGR-1是一種專門的XP受體，它在配體結合時發出信號，促進吞噬小體破裂。這允許吞噬體內容物逃逸到胞漿中，在那裡它們進入內源性主要組織相容性複合體I類抗原加工途徑。DNGR-1的活性映射到其信號結構域，激活SYK和NADPH氧化酶，即使與異源受體拼接並在異源細胞中表達，也能引起吞噬損傷。我們的數據揭示了固有免疫受體的存在，它將配體結合到胞內囊泡損傷上，以允許MHC-I類抗原呈遞外源抗原，並調節適應性免疫。
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