Talented and motivated students passionate about doing research are invited to apply for this PhD position. The successful applicant will join the Crick PhD Programme in September 2022 and will register for their PhD at one of the Crick partner universities (Imperial College London, King’s College London or UCL).
This 4-year PhD studentship is offered in Dr Victor Tybulewicz’s Group based at the Francis Crick Institute (the Crick).
The adaptive immune system is essential for defence against infection and for the generation of immunological memory which protects the organism from re-infection and forms the basis of effective vaccination. The hallmark of the adaptive immune response is the generation of high-affinity pathogen-specific antibodies.
The lynchpin of this response is communication between antigen-specific B cells and T cells. B cells bind protein antigen through the B-cell antigen receptor (BCR), internalise and degrade it, and present resulting antigenic peptides on surface MHC class II molecules. Signalling from the BCR results in upregulation of CD80 surface expression. The T cell binds to peptide-MHC complexes on the B cell through its T-cell antigen receptor (TCR), while CD28 on the T cell binds to CD80 on the B cell (Figure). Signalling from TCR and CD28 results in surface expression of CD40 ligand (CD40L) that binds to CD40 on B cells, triggering strong activation signals in the B cell. Further pairs of cell surface molecules that are essential for this two-way communication between B and T cells include ICOS and ICOSL, and OX40 and OX40L (Figure).
This project will investigate the signalling pathways operating during B cell-T cell communication. Firstly, you will determine the nature of the signals transduced by ICOSL into B cells, a process about which almost nothing is known. You will use biochemical and proteomic methods to investigate signalling induced by ICOSL, and to identify proteins bound to the cytoplasmic domain of ICOSL. This will be combined with genetic mutations to establish causal mechanisms, for example using mice with mutations in the cytoplasmic domain of ICOSL or CRISPR/Cas9 to inactivate signalling proteins identified in the proteomic analysis and testing the effect of these mutations on antibody responses in vivo.
Secondly, you will search for new unknown pairs of signalling receptors on the surface of B and T cells that are required for inter-cellular communication and the resulting antibody response. This will involve proteomic identification of surface proteins and CRISPR/Cas9 screens of candidate genes to discover novel signalling pathways controlling B-T interactions.
Supported by an experienced postdoc, you will use a range of techniques including mouse genetics, immunology, biochemistry, CRISPR/Cas9 mutagenesis, proteomics and RNAseq – our lab has expertise in all of these. An ICOSL-deficient mouse strain is available for this work.
Candidate background
This project would suit candidates with a degree in biological or biomedical sciences or similar. The students should have an interest in or knowledge of immunology, biochemistry, genetics, bioinformatics or cell biology.
Applicants should hold or expect to gain a first/upper second-class honours degree or equivalent in a relevant subject and have appropriate research experience as part of, or outside of, a university degree course and/or a Masters degree in a relevant subject.
APPLICATIONS MUST BE MADE ONLINE VIA OUR WEBSITE (ACCESSIBLE VIA THE ‘INSTITUTION WEBSITE’ LINK ABOVE) BY 12:00 (NOON) 11 November 2021. APPLICATIONS WILL NOT BE ACCEPTED IN ANY OTHER FORMAT.
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