Structure the of TCR594-HLA-DQ2.2:DQ2.2-glut-L1 ternary complex.
“The coeliac disease associated molecules HLA-DQ2.5 and HLA-DQ2.2 are highly homologous. Despite their close sequence similarity, ~95% and <1% of coeliac disease patients are HLA-DQ2.5+ and HLA-DQ2.2+, respectively. We determined the molecular basis of how a single amino acid polymorphism confers the marked differential association of these two HLA-DQ variants with coeliac disease.”
Within this theme, conceptual challenges lie in understanding how the T cell antigen receptor co-recognises peptide determinants while being presented by molecules encoded by the Major Histocompatibility Complex (MHC) – both in the context of protective immunity (e.g. to viruses) and aberrant immunity (e.g. autoimmunity). The Imaging CoE’s strategy is to develop reagents to characterise peptide-specific T-cells ex vivo and then use atomic and molecular imaging-based techniques to investigate the structural basis underpinning the interactions by the T-cell receptor (TCR).
PROF. JAIME ROSSJOHN
AT A GLANCE
Our work in 2020 has led to:
- An increased understanding of the role that a single polymorphism in MHC can play in the susceptibility to inflammatory diseases such as coeliac disease (Ting et al. PNAS 2020).
- Determining that the protective CD8+ cytotoxic T cell response to SARS-CoV-2 in COVID19 patients is sub-optimal compared to that observed for other viral infections such as influenza, suggesting novel strategies need to be considered in the design of SARS-CoV-2 vaccines (Habel et al. PNAS 2020).
- Demonstrating how parameters other than the specific TCR-MHC interaction can influence binding behaviour at cell-cell contacts (Junghans et al, Journal of Cell Science 2020).
FUTURE OUTLOOK
We continue to explore the molecular basis and impact of antigen recognition of peptide-MHC on protective and a berrant immunity.