Dendritic cells (DC) use a variety of cell surface receptors to monitor the environment for potential dangers, including cells that have died of non-homeostatic causes (eg. infected cells), to induce appropriate immune responses. We recently identified Clec9A, a novel DC-specific Damage-Associated Molecular Pattern receptor that is expressed by mouse and human cross-presenting DC subsets.
Clec9A recognises dead cells and plays an important role in the recognition and processing of dead cell-derived Ag. Our research has focussed on identification of Clec9A ligands, and determining the molecular basis of Clec9A recognition of dead cells. We identified that Clec9A recognises a cytoskeletal component of cells that is conserved across species, and only exposed upon cell membrane damage. We further identified this Clec9A ligand as a filamentous form of actin in association with actin-binding domains of key cytoskeletal proteins. We have recently identified a novel Clec9A interacting protein that appears to regulate ubiquitination of Clec9A complexes, thereby targeting Clec9A complexes for downstream processing. Our research is currently focussed on characterising the molecular interactions that underpin Clec9A function, the role of these interactions in mediating immune responses, and the potential of targeting Clec9A for immune therapy.