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Kennedy Trust Prize Studentships

Project outline

In tissues, stromal fibroblasts interact with leukocytes to form functional cellular niches that regulate inflammatory immune responses.  While targeting leukocytes and their products has been an effective strategy for the treatment of several different immune mediated inflammatory diseases (IMID), many patients fail to acheive remission thus the need to develop novel therapeutic strategies.  Targeting stromal cell cells has the potential to be key strategy in therapy resistant autoimmune and inflammatory disease.  Thus, understanding factors that regulate these niches and the mechanisms regulating their function is an important aim. 

We have recently identified type II cytokines IL4/IL13 produced by specialised tissue resident leucocytes and their cognate receptors on fibroblasts as key pathways that differentially regulate the activation, proliferation, migration and differentiation of tissue resident fibroblasts into pathogenic stromal cells.  One of the key cell types we have identified and which produce  IL13 are innate lymphoid cells type II (ILC2s).  Recently it has been shown that ILC2 closely associate with neurons to produce specialised neuro-immune cell units (NICs) that provide a link between the peripheral and central nervous system and peripheral immune responses.  The communication between leukocytes and neurons may have a key role in regulating formation and severity of rheumatoid arthritis and other IMIDs and help explain long standing but poorly undersood observations of a linke between the nervous system and outcome in RA; patients with a stroke have less severe arthritis on the side of the body affected..

Stromal cells and leukocytes express receptors for neural derived peptides. Conversely neurons express TLR receptors permitting direct responses to immunological challenge providing a potential mechanism of localised cross talk between peripheral neurons and leukocytes.  Signals derived from the CNS regulate global glucocorticoid and hormone production by the liver, spleen and kidney in response to circadian control providing a secondary level of neuronal control of localised immune responses.  The role of neurons in stromal cell – leukocyte cross talk in IMIDs is unknown.  Work in the Coles and Buckley labs utilises interdisciplinary approaches using a combination of primary human tissues, mouse models and systems based approaches to understand mechanisms regulating stromal cell function in IMIDs.  The group combines cutting edge imaging technologies from single molecule resolution to 4D whole tissue imaging with single cells genomics, functional assays and computational models to understand mechanisms regulating stromal cell function.

To  determine the relevance of neuronal – immune cell cross talk this project will utilise 3D imaging of innate immune cells, stromal and neurons to analyse NICs in tissue sites of IMIDs including human peripheral synovial lining. This will be combined with single cell genomics of all three cell types to identify which cell types express different ligands and receptors regulating the cross talk between neurons, leukocytes and stromal fibroblasts.  This data will be utilised to inform both in vitro 3D human cell culture systems and in vivo mouse knock out models of key regulators of the cross talk. These transgenic  mice will be used to determine the specific role of pathways regulating IMID progression, a specific focus of this project will be in rheumatoid arthritis.  From these model systems, this PhD project will provide new insights into how immune cell niches are regulated and how local and central nervous cells co-ordinate the outcome of immune responses.  This will provide insights into how the nervous system regulates inflammatory immune responses and how those subsequent responses can in turn regulate neuronal function.

Students interested in this project will benefit from close integration and collaboration with a multidisciplinary team of experimental scientists, systems biologists, clinicians, and work closely with the Arthritis - Therapy Acceleration Program (A-TAP), a joint program between the University of Oxford and Birmingham.

Students will be based at the Kennedy Institute of Rheumatology, where they will benefit from state-of-the-art molecular and cell biology, flow cytometry, imaging infrastructure supported by a strong systems biology infrastructure. This project is ideally suited to a student with a strong molecular / cell biology background and an interest in both immunology and neurobiology. The student will have an opportunity to develop their computational skill-set to analyse data generated from single cells RNA-seq and imaging experiments and work in a group with a mix of computational/mathematical immunologists.

Training Opportunities

The Kennedy Institute of Rheumatology is a world-renowned research centre and is housed in a brand new state-of-the-art research facility. It is ideally situated on the Old Road Campus next to the Ludwig Institute for Cancer Research, the Jenner Institute, the Wellcome Trust Centre for Human Genetics, and the Big Data Institute. Training will be provided across the range of cell, molecular, and bioinformatics techniques. A core curriculum of 20 lectures will be taken in the first term of year 1 to provide a solid foundation in musculoskeletal sciences, immunology and data analysis. Students will attend weekly departmental meetings, journal clubs, and will be expected to attend seminars within the department and those relevant in the wider University. Subject-specific training will be received through our group's weekly lab meetings. Students will also attend external scientific conferences where they will be expected to present the research findings.

Relevant Publications

  1. Rao DA, et al., Pathological expanded peripheral T helper cells subset drives B cells in rheumatoid arthritis, Nature, 542(7693): 110-114, 2017
  2. Chimen M. et al., Homeostatic regulation of T cell trafficking by a B cell-derived peptide is impaired in autoimmune and chronic inflammatory disease, Nature Medicine 2(15): 467-475, 2015
  3. Li Z. et al., Epidermal Notch1 recruits RORγ(+) group 3 innate lymphoid cells to orchestrate normal skin repair. Nature Communications. 2016 Apr 21;7:11394
  4. Hoorweg K. et al., A stromal cell niche for human and mouse type 3 innate lymphoid cells, Journal of Immunology, 195(9) 4357-4263, 2015.

Scientific Themes

  • Stromal Immunology, Rheumatoid Arthritis, Neural – Immune cell Interactions, Tissue Inflammation

Further information

Professor Mark Coles, Kennedy Institute of Rheumatology, University of Oxford

Professor Christopher Buckley, Kennedy Institute of Rheumatology, University of Oxford

 

Project reference number #201807

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