2011 ESCI Award for Excellence in Basic / Translational Research: innate regulation of adaptive immunity by dendritic...

Dendritic cells (DC) play a key role in the initiation of adaptive immunity, and the manipulation and/or targeting of DC has great potential for immune intervention. However, clinical applications are hampered by the fact that we still know relatively little about how DC become 'activated' to stimulate and direct T-cell responses. Over the last decade, much emphasis has been placed on dissecting innate signalling pathways that can trigger DC activation and promote T-cell priming. Here, we review work from our laboratory aimed at helping define 'pattern-recognition pathways' involved in DC activation by potential pathogens. One pathway for sensing infection by RNA viruses involves recognition of viral genomes or virally infected cells in endosomal compartments and utilises members of the toll-like receptor (TLRs) family, including TLR9, 7, or 3. RNA virus genomes can additionally be recognised in the cytosol by DExD/H-box helicases such as MDA5 or RIG-I, the latter of which is activated by RNAs bearing 5' tri-phosphates. Finally, a distinct pathway involves cell surface and phagosomal recognition of fungi by C-type lectins, which signal via Syk kinase. Notably, some of these pathways are involved not only in direct sensing of pathogens but also in the recognition of self-alterations that might accompany infection, such as induction of cell death. 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.