The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia.
Immunity. 2012 Apr 20;36(4):646-57. doi: 10.1016/j.immuni.2012.03.009. Epub 2012 Apr 5.
The immune system must distinguish viable cells from cells damaged by physical and infective processes. The damaged cell-recognition molecule Clec9A is expressed on the surface of the mouse and human dendritic cell subsets specialized for the uptake and processing of material from dead cells. Clec9A recognizes a conserved component within nucleated and nonnucleated cells, exposed when cell membranes are damaged. We have identified this Clec9A ligand as a filamentous form of actin in association with particular actin-binding domains of cytoskeletal proteins. We have determined the crystal structure of the human CLEC9A C-type lectin domain and propose a functional dimeric structure with conserved tryptophans in the ligand recognition site. Mutation of these residues ablated CLEC9A binding to damaged cells and to the isolated ligand complexes. We propose that Clec9A provides targeted recruitment of the adaptive immune system during infection and can also be utilized to enhance immune responses generated by vaccines.
免疫系统必须区分存活细胞和因物理和感染过程而受损的细胞。受损细胞识别分子 Clec9A 表达在专门摄取和处理来自死亡细胞物质的小鼠和人类树突状细胞亚群的表面。Clec9A 识别核细胞和无核细胞内保守的成分，当细胞膜受损时暴露出来。我们已经确定这种 Clec9A 配体是与细胞骨架蛋白的特定肌动蛋白结合域相关联的丝状形式的肌动蛋白。我们已经确定了人 CLEC9A C 型凝集素结构域的晶体结构，并提出了具有保守色氨酸的功能二聚体结构在配体识别位点。这些残基的突变消除了 CLEC9A 与受损细胞和分离的配体复合物的结合。我们提出，Clec9A 在感染期间提供适应性免疫系统的靶向募集，并且还可以用于增强疫苗产生的免疫反应。
