The three Rs of innate immune recognition: Toll like receptors (TLRs), RIG-like receptors (RLRs) and Nod-like receptors (NLRs)

Information about the chairs

Over the past few years the Triantafilou group has been focusing on unravelling the molecular mechanisms behind the innate recognition of bacterial as well as viral pathogens. In particular, we have focused on the involvement of the Toll-like receptor (TLR) family of proteins, a recently identified family of pattern recognition receptors (PRRs), in the innate immune sensing. We have the expertise and the research tools for investigating receptor interactions using bio-imaging techniques, such a Fluorescence Resonance Energy Transfer (FRET), Fluorescence Recovery after Photobleaching (FRAP), Single Particle Imaging (SPFI), Single Particle Tracking (SPT), Fluorescent Loss in Photobleaching (FLIP) as well as live cell imaging. Using combinations of these techniques, our group has discovered novel concepts in innate immune recognition of microbial ligands by TLRs and co-operating PRRs. We have been one of the first to demonstrate that the single-receptor concept of innate immune recognition is an oversimplified one and that different combinational associations of receptors determine the innate immune response to different microbial pathogens, using a range of non-invasive biophysical techniques. We performed several studies investigating associations of PRRs in response to bacterial products from Helicobacter pylori,Neisseria meningitidis, and bacterial lipopeptides. Furthermore, we demonstrated that membrane microdomains, or "lipid rafts" play an important role in this receptor cluster formation by providing a microenvironment for these interactions to take place. This was the first ever publication demonstrating that TLRs exist and signal within lipid rafts (making this paper one of the most cited papers in the field). We provided the first dynamic picture of TLR engagement by their ligand by determining the lateral diffusion of receptors involved in the innate immune response before and after stimulation by bacterial products . It has helped us understand the organisation, lateral mobility and confinement of PRRs involved in the innate immune response on the plasma membrane.  In addition, using fluorescent imaging, we have revealed that TLR2 exists as a heterodimer prior to ligand engagement, as well as its intracellular trafficking and targeting in response to Gram-positive bacterial products. More recently, we have demonstrated that CXCR4 acts as a negative regulator for TLR2 and its significance in the innate recognition of Porphyromonas gingivalis (Hajishengallis et al. 2008). This was the first study demonstrating that TLR2-CXCR4 association can impair innate immune responses. Finally, we have shown that TLR4, TLR7 and TLR8 are involved in sensing viral products. These were the first studies to reveal how enteroviruses are recognised by the innate immune system. 

About the Speakers

Tom Monie did his PhD in the Molecular Virology of Retroviruses at Cambridge and then moved to Imperial College to study the structure and function of translation initiation factors. He returned to Cambridge, changing fields once again to work with Dr Nick Gay on the role of TLRs in innnate immunity. Since October 2008 he has held a Wellcome Career Development Fellowship to study the mechanisms of ligand recognition and signal transduction in the NLRs NOD1 and NOD2.