Immune response and danger signals
The aim of our work is to investigate how intracellular TLR trafficking and signalling are regulated at the steady state and during inflammation 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. 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.
Our main objectives are:
- To identify new partners of interaction for UNC93B1 and to investigate the molecular mechanisms by which UNC93B1 shapes their function.
- To evaluate the actions of TLR9 in microglia versus peripheral immune cells during development of AD using specific models of mice lacking TLR9 and in human AD pathology.
- To investigate the role of TLR9 in immune tolerance and response to cancer.