BBSRC NLD Doctoral Training Partnership: Structural understanding the mechanisms of co-presentation of unconventional HLA ligands and chemicals

T-cells, the drivers of adaptive immunity, have great therapeutic potential. However, there are still many unknowns about how they are activated. It is well understood that T-cells respond to antigens which have been processed and presented as antigenic peptides by molecules called “human leukocyte antigens” (HLA). However, chemical compounds can interfere with this process, resulting in the formation of neo-antigens which have not been seen by the immune system before, potentially harming self- tissues. HLA molecules generally present peptides containing 8-11 amino acid residues. However, in the presence of chemicals, unconventional antigens such as di- and tri-peptides conjugated with chemicals or the chemical itself can be presented by HLA proteins. The mechanisms of this presentation remain largely unknown. In this project, we aim to better understand how neo-antigens are presented in the presence of certain chemicals, and how chemical associated neo-antigens are recognised by human T-cells. To achieve this, these peptide antigens will be eluted from the surface of HLA molecules on cells and tissues and subsequently characterised using mass spectrometry-based methods. Chemical compounds that have known genetic associations with specific HLA alleles will be used as model compounds to explore pathways of neo-antigen formation. The crystals of HLA proteins in complex with unconventional antigens will be generated to explore the interaction between neo-antigens and HLA molecules. Finally, the potential T- cell immunity of identified neo-antigens will be assessed using human T- cells from healthy volunteers or patients with specific diseases.

The departments of Pharmacology and biochemistry at the University of Liverpool in collaboration with the Department of Biosciences at Durham University present an exciting multidisciplinary PhD opportunity. This multi-centre and multi-disciplinary project is suited for a student with an interest in analytical chemistry/biochemistry/ computational biology/cell biology from a relevant degree background (e.g. biological sciences, medicinal chemistry, and immunology). The student will be trained in both immunopeptidomics and mass spectrometry methods in parallel with learning how to generate protein crystals. Furthermore, some wet-lab training will also be provided in genomics and T-cell culture methods. Finally, the student will have an opportunity to spend three months at the University of Durham to study the biochemical and cell biological mechanisms of antigen processing. Upon completion, the student will have first-hand training in a range of analytical techniques relevant to academia and industry alike.

HOW TO APPLY:

Applications should be made by emailing bbsrcdtp@liverpool.ac.uk with:

• a CV (including contact details of at least two academic (or other relevant) referees);
• a covering letter – clearly stating your first-choice project, and optionally 2nd ranked project, as well as including whatever additional information you feel is pertinent to your application; you may wish to indicate, for example, why you are particularly interested in the selected project(s) and at the selected University;
• copies of your relevant undergraduate degree transcripts and certificates;
• a copy of your passport (photo page).

A GUIDE TO THE FORMAT REQUIRED FOR THE APPLICATION DOCUMENTS IS AVAILABLE AT https://www.nld-dtp.org.uk/how-apply. Applications not meeting these criteria may be rejected.

In addition to the above items, please email a completed copy of the Additional Details Form (as a Word document) to bbsrcdtp@liverpool.ac.uk. A blank copy of this form can be found at: https://www.nld-dtp.org.uk/how-apply.

Informal enquiries may be made to xlmeng@liverpool.ac.uk

The deadline for all applications is 12noon on Monday 22nd July 2024.

Part-Time Study Options

All NLD DTP PhDs are available as part time or full time, with part time being a minimum of 50% of full time. Please discuss potential part time arrangements with the primary supervisor before applying to the programme.

Project CASE Status

This project is not a CASE project. While individual applicant quality is our overriding criterion for selection, the NLD DTP has a commitment to fund 8 CASE projects per year - as such, CASE projects may be favoured in shortlisting applicants when candidates are otherwise deemed to be equal or a consensus on student quality cannot be reached.