Research Projects

Recently the Godfrey group have identified a new class of non-lipid based compounds capable of stimulating human NKT cells. Our preliminary data reveal a new mechanism through which NKT TCRs can recognise non-lipid molecules when bound to CD1d presenting the self-lipid “sphingomyelin”. This implies that non-lipid compounds can alter the reactivity to CD1d-lipid complexes by some NKT cells, through a mechanism that is reminiscent of “abacavir hypersensitivity syndrome” through which this drug alters how self-peptides are presented to conventional T cells to trigger an undesired immune response. Furthermore, our preliminary data uncovers a previously unexplored population of NKT cells in humans with unknown function in the immune system. Such observation opens a new area of research in immunology and has important clinical implications, as the core structure of these particular CD1d-binding non-lipid Ags is similar to that of ‘sulfa-drugs’, which represent a valuable family of anti-microbial and anti-inflammatory drugs for decades, and yet can sometimes cause severe delayed hypersensitivity reactions in patients. This suggests a role for CD1-restricted T cells in these poorly understood reactions, that occur through unknown mechanism, presumed to be “T cell mediated”.

This project will assess whether there is scope for these small drugs to bind other CD1-lipid presenting proteins (CD1a, b, c) and whether there are subsets unconventional (CD1a/b/c-restricted) T cells that can sense this, similar to how we have shown to occur for some CD1d-restricted NKT cells. This will involve a combination of protein chemistry, development of tools to identify these cells using flow cytometry and assess their functional potential. PCR and sequencing techniques will be used to investigatetheir TCR repertore. Importantly, having established a collaboration with a clinician at the Austin, we will have access to samples from sulfa-drug hypersensitivity patients which will also allow us to investigate for the first time the scope for Unconventional T cell reactivity in these cases. Ultimately this might eventually lead to the development of novel diagnostics and therapies that may prevent such reactions to this valuable family of drugs.

Contact project supervisor for further
information and application enquiries