Research Projects

CD1-proteins are best-known for their ability to present lipid-Ags to subsets of CD1-restricted unconventional T cells, which do not recognise peptides nor MHC-proteins. In humans there are four CD1 proteins (CD1a-d) that traffic to the surface of Ag-presenting cells. We recently employed a CRISPR/Cas9 genome wide screen to reveal the breakthrough finding that CD36 family members (CD36, SR-B1, and LIMP-2) bind to CD1b, CD1c and CD1d, but surprisingly, not CD1a (Gherardin et al, Sci Immunol 2021, PMID:34172588). These ligands are abundantly expressed in blood cells (inc. platelets/erythrocytes/B-cells/monocytes) and are implicated in human diseases including atherosclerosis and Alzheimer’s. A subsequent study (Brailey et al Nat Comms 2022, PMID:36344546) found that this interaction plays an important role in regulating immunity by controlling the metabolic state of CD1-presenting macrophages. We have now revealed a new interaction with CD1-proteins that appears to be restricted to an unknown receptor expressed by certain cancers. This proposal aims  to identify and characterise that receptor by employing a similar appproach to that in our previous study. This involves screening a CRISPR-KO library (flow cytometric sort of cells that carry a mutation that confers loss of the receptor) to identify candidate target genes. This will be done with bioinformatics support from CTI, and with gene KO/gene rescue ex periments to validate targets. There is scope to collaborate with strucutral biologists to further characterise this interaction. The knowledge gain derived from this proposal will open new research streams to understand the biological significance of this yet undescribed interaction. Further, it may offer new avenues to explore new cancer therapies or ways to manipulate CD1-mediated responses in immunity. 

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