Neo-antigen challenge to uncover the formation and persistence of CD4 T resident memory cells in humans

This DPhil (PhD) in Molecular and Cellular Medicine will seek to understand how tissue-resident memory CD4 T (T_RM) cells establish themselves in tissues in response to a newly encountered antigen. T_RM are a type of long-lived memory cell type that, unlike most T cells, do not circulate around the body, but take up residence in specific tissues. In mice, these cells are known to be key in mediating immunity to infection and vaccination. However, their development and function are less well established in humans.

The project will rely on human immune challenge (HIC) models using the CD4 T cell dependent neo-antigen keyhole limpet hemocyanin (KLH). Given the lack of natural existing immunity to KLH in humans, this enables the tracking of newly formed memory T cells across time and space. In addition, using the skin as a rechallenge site allows the interaction between tissue stroma and memory T cells to be explored. Thus, we can understand how the tissue microenvironment orchestrates the establishment of long-term immune memory.

During this DPhil, you will work as part of a collaborative, interdisciplinary team in supporting the conduct of KLH HIC studies enrolling healthy volunteers and the processing the blood, skin and lymph node samples derived from them. You will use these samples for next-generation sequencing, multiparameter spectral flow cytometry, imaging and computational analysis to study CD4 T cell tissue-resident memory formation in humans. Specifically, the 3-year DPhil will include:

• A critical literature review on current understanding of tissue-resident adaptive immunity and the mechanistic drivers.
• Formation of a temporal and spatial cellular atlas (bulk and/or single-cell/nuclei RNA-sequencing) of a neo-antigen response in the circulation, lymphatics and skin in humans. You will focus on TCR-sequencing which will enable tracking of KLH-specific T cells over time and space.
• Detailed spatial analysis of human T_RM and surrounding cell types using state-of-the-art mass spectrometry microscopy techniques.
• Potential development of MHCII tetramers to track KLH-specific T cells and to use in ex vivo and in vitro functional models assessing T cell function.

Training 

The Nuffield Department of Orthopaedics, Rheumatology, and Musculoskeletal Sciences (NDORMS) hosts scientists working in diverse areas, enabling and encouraging research and education into the causes of multiple disease states and how best to treat them. The successful applicant will benefit from regular hands-on training and supervision by experienced laboratory and clinical scientists based primarily at the Botnar Research Centre, but also work closely with teams based in the Kennedy Institute of Rheumatology. Training will be provided in “wet-lab” techniques including, flow cytometry, transcriptomics, histochemistry, ELISA, ELISpot, and in vitro cell cultures of human immune cells. Unique exposure to human experimental medicine studies, specifically immune challenge, will be afforded along with training in their conduct and delivery. Funding for this project is provided by UCB and there will be frequent opportunities to interact with and/or spend time at the industrial partner accruing valuable industrial experience.

A core curriculum of lectures will be taken in the first term to provide a solid foundation in a broad range of subjects including musculoskeletal biology, inflammation, epigenetics, translational immunology, data analysis and the microbiome. Students will also be required to attend regular seminars within the Department and those relevant in the wider University. 

Students will develop their ability to project manage and build scientific communication and dissemination skills by presenting regularly in lab meetings and departmental seminars, and by attending external conferences to present their research globally, with limited financial support from the Department. 

Students will have access to various courses run by the Medical Sciences Division Skills Training Team and other Departments. All students are required to attend a 2-day Statistical and Experimental Design course at NDORMS and run by the IT department (information will be provided once accepted to the programme).

Key publications: 

Jiang, X., Clark, R., Liu, L. et al. Skin infection generates non-migratory memory CD8⁺ T_RM cells providing global skin immunity. Nature 483, 227-231 (2012).

Pallett, LJ. et al. IL-2^high tissue-resident T cells in the human liver: Sentinels for hepatotropic infection. J Exp Med 214(6): 1567-1580 (2017).

Drennan, PG. et al. In vivo human keyhole limpet hemocyanin challenge in early phase drug development: A systematic review. Clin Transl Sci 16(3): 357-382 (2023).

Keywords 

Immunology, human, immune challenge models, T cells, immune memory, resident immunity 

Research Group and Supervision Team

The project will be supervised by a team of experienced researchers and experts in the field of human immunology and clinical pharmacology. A/Prof James Fullerton is Associate Professor of Clinical Therapeutics and heads the Translational Pharmacology team at the Botnar Research Centre. He will be the main supervisor for the DPhil project. Dr Roel De Maeyer is an Oxford-BMS Translational Fellow and will provide oversight on T cell biology in human immune responses. Prof Mark Coles is Professor of Immunology based at the Kennedy Institute of Rheumatology and will provide insight into stromal-immune interactions. Prof Tao Dong is the Ita Askonas Professor of Translational Immunology and the founding director of the Chinese Academy of Medical Sciences Oxford Institute (COI). She will lead assessment of the TCR repertoire and T cell memory function.

Scholarship

This is a fully-funded 3-year DPhil project, supported by UCB. The scholarship covers the equivalent of UK tuition fees and provides a stipend to support living costs. If you are applying as an overseas candidate, you must be able to cover the difference between home and overseas fees. The successful candidate will be associated with St Hilda’s College. 

How to Apply

Please contact the relevant supervisor(s), to register your interest in the project, and the departmental Education Team (graduate.studies@ndorms.ox.ac.uk), who will be able to advise you of the essential requirements for the programme and provide further information on how to make an official application.

Interested applicants should have, or expect to obtain, a first or upper second-class BSc degree or equivalent in a relevant subject and will also need to provide evidence of English language competence (where applicable). The application guide and form is found online and the DPhil will commence in October 2025.

Applications should be made to one of the following programmes using the specified course code:

D.Phil in Molecular and Cellular Medicine (course code: RD_MP1)

For further information, please visit http://www.ox.ac.uk/admissions/graduate/applying-to-oxford.