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Mechanisms of T cell mediated killing

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  • Full or part time
    Dr M Harkiolaki
    Prof M Dustin
    Dr A Gérard
  • Application Deadline
    No more applications being accepted
  • Funded PhD Project (European/UK Students Only)
    Funded PhD Project (European/UK Students Only)

About This PhD Project

Project Description

An important function of the immune system is to kill infected and cancerous cells. Cytotoxic lymphocytes using adaptive and natural recognition mechanisms use shared sets of effector mechanism - one based on the cooperative function of secreted proteins perforin and granzymes. Defects in this mechanism not only leave the host vulnerable to infection, but lead to profound defects in immune regulation and development of auto-inflammatory diseases. Perforin and granzymes are released from intracellular stores into the small space between the CTL and target cells, the immunological synapse, but there state of matter involved- whether soluble proteins or a solid particle, was not known. We have discovered in studies carried out in part on B24 that CTL actually release perforin and granzyme B in the core of ~100 nm particles that are surrounded by a carbon dense shell. We refer to these particles are core-shell supramolecular attack particles (SMAPs). Many questions remain about how these particles are formed inside CTL, how they are released and how they interact with target cells to mediate killing. There is also a possibility that SMAPs may be engineered to make them more specific for tumours- developing a new form of tumour immunotherapy.

A student co-supervised by Prof Mike Dustin at Oxford and Dr. Maria Harkiolaki at B24 would have a transformative impact on this line of research and greatly increase the pace of discovery. The Cryo-Soft X-ray Tomography (CSXT) technology has provided unique information about these particles that complement work of Dr. Balint in Prof Dustin’s lab using super-resolution Stochastic Optical Reconstruction Microscopy. The potential for a student to perform correlative Cryo-Structured Illumination Light Microscopy (Cryo-SIM) and CSXT on this new and unique biological particle will provide an excellent training opportunity and lead to transformative discoveries with implications beyond the immune system into human biology.

Research techniques: CSXT, Cryo-SIM, Total internal reflection microscopy (TIRFM) and STORM, immunological and biochemical techniques, SLB systems, cellular immunology, genome editing.

Student training: Oxford: primary human cells and mammalian cell lines, CRISPR/Cas9 genome editing, SLB system, production and capturing of cytotoxic vesicles on SLB and their validation by biochemistry techniques, sample preparation for TIRFM and STORM, data processing and analysis. Diamond: sample preparation and data acquisition (CSXT, Cryo-SIM, Cryo-STORM), data processing, analysis and segmentation.

Contact:
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