ID: 9: Dendritic cells in immunity to infection and cancer

Abstract

Direct sensing of pathogen components is a major trigger of dendritic cell (DC) activation, leading to innate and adaptive immunity. Over the years, we have studied multiple pattern-recognition pathways that mediate DC activation. One pathway for sensing infection by RNA viruses involves recognition of viral genomes or virallyinfected cells in endosomal compartments and utilises members of the toll-like receptor (TLRs) family, including TLR9, 7, or 3. Viral genomes can additionally be recognised in the cytosol by DExD/H-box helicases such as RIG-I, which are activated by RNAs bearing 5’ tri- and di-phosphates. Finally, a distinct pathway involves cell surface and phagosomal recognition of fungi by C-type lectins, which signal via Syk kinase. Notably, we have recently found that some Syk-coupled C-type lectins are involved in functions other than microbial recognition by DC. One, CLEC-2, allows DCs to relax lymph node stromal cells, permitting expansion of lymph nodes upon inflammation. Another, DNGR-1, allows DCs to detect dead cells by binding exposed F-actin and facilitates cross-presentation of dead cell-associated antigens. Interestingly, DNGR-1 marks CD8 α + DCs, a specialised subtype of DCs in mice and their human equivalents. DNGR-1 additionally can be used to fate map DCcommitted precursors in mouse to define DCs by ontogeny. These studies help build a global picture of the receptors and signalling pathways that regulate DC activation and have applications in immunotherapy of cancer and infectious diseases.