The main focus of my laboratory is to investigate the regulation of innate immune sensors such as Toll-like receptors in dendritic cells
Toll-like receptors (TLRs) recognize microbial products and play an essential role in innate and adaptive immunity. TLRs are divided in two families: membrane TLRs which sense the presence of proteins and lipids from bacteria and intracellular TLRs (TLR3, 7 and 9) localized in endosomes which, engage single stranded, double stranded RNA and methylated CpG DNA respectively from pathogens. In the absence of stimulation, intracellular TLRs are retained in the endoplasmic reticulum (ER) together with another ER resident protein, UNC93B1. Following nucleic acids sensing, intracellular TLRs traffic to endosomes where they require proteolytic cleavage to be functional and recruit the adaptor proteins MyD88 and TRIF. Their signalling which, leads to the production of pro-inflammatory cytokines and cell surface expression of co-stimulatory molecules, is essential to induce adaptive immunity in dendritic cells (DCs). The molecular chaperone UNC93B1 is essential for TLRs folding and trafficking and also set their activation threshold. Indeed, excessive TLR7 or TLR9 signalling can lead to autoimmunity and death. Thus, characterizing new factors involved in TLRs signalling is crucial in determining what influences the outcome of the immune response. The aim of our work is to further investigate how intracellular TLR trafficking and signalling are regulated at the steady state and following pathogen infection in DCs.
The overall goals are:
Bénédicte Manoury studied biochemistry and cell biology at University Pierre and Marie Curie in Paris. She was awarded a PhD in Immunology at University René Descartes and an EMBO long-term fellowship to do her post-doctorate in the laboratory of Pr C Watts in Dundee studying antigen presentation in dendritic cells. She came back to Paris to start her own team in 2004 supported by an AVENIR grant (INSERM). She is now the head of the group « Immune response and Danger signals » at Institut Necker Enfants Malades where she investigates Toll-like receptor activation in cancer and infectious diseases.