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KIRC7: Tissue-resident CD8+ T cell and fibroblast cross-talk in juvenile idiopathic arthritis


   Kennedy Institute of Rheumatology

  ,  Friday, December 03, 2021  Funded PhD Project (Students Worldwide)

Oxford United Kingdom Immunology

About the Project

Oligoarticular juvenile idiopathic arthritis (JIA) is the commonest type of inflammatory arthritis in those under 16 years. In a majority of these patients, a single joint is affected at presentation and localised repeat inflammation occurs at certain joints, implicating resident cell populations and the microenvironment in disease pathogenesis. In oligoarticular JIA inflammation may resolve completely, persist in the same pattern of joint involvement or severely extend to affect multiple small and large joints. There is evidence to suggest that strong early treatment may limit the severity of disease, however an inability to differentiate likely disease course means many patients do not start strong immunosuppression until later in their disease. Persistent cell populations of tissue-resident CD8+ memory T cells and fibroblasts have been identified from murine models, capable of priming the joint towards an exaggerated inflammatory response. These cells resist systemic treatment and reside in the joint during remission, recruiting and activating immune cells to amplify inflammatory response. Cells with this tissue-resident CD8+ memory T signature are significantly enriched in the synovial fluid of patients with inflammatory arthritides and our pilot data suggests they are also enriched in JIA. We have established funding to study the transcriptomic and proteomic profile of peripheral blood, synovial biopsies and fluid cells from 40 paediatric patients with JIA, at a single-cell level. In co-culture, synovial fibroblasts and T lymphocytes from patients with rheumatoid arthritis are able to mutually induce cytokines that increase the adhesion, survival, metabolic programming and activation state of the T lymphocytes. These cytokines are some of the most highly detected concentrations of cytokines detected from the plasma of JIA patients. Therefore we aim to explore the relevance of these cell populations to the disease course with the aim of improving prognosis and ultimately therapeutic targeting. Specifically in the project you will

  • Characterise the phenotype of CD8+ T lymphocyte subsets and fibroblasts of the inflamed joint from young people with juvenile idiopathic arthritis (JIA).
  • Determine if differences in disease outcomes of oligoarticular JIA can be predicted from variation in tissue-resident CD8+ T cell and fibroblast populations at an early stage.
  • Functionally assess how tissue-resident T lymphocytes interact with fibroblasts in the inflamed joint.

TRAINING OPPORTUNITIES:

The Kennedy Institute is a world-renowned research centre and is housed in a brand new state-of-the-art research facility. Training will be provided in techniques in a wide range of immunological tool kits (cell isolation, FACS, ELISA, primary cell culture) and imaging (immunofluorescence on tissue sections) approaches. Specifically you will develop key expertise in (1) Bioinformatic analyses with single-cell RNA sequencing, CITE-seq, TCR-sequencing (as part of the MAPJAG cross-site study) and deconvolution of bulk-RNA seq (RSS study). (2) Cellular phenotyping with in vitro assays, detailed genomic panels (10X Genomics), immunofluorescence and flow cytometry sorting, (3) in vitro tissue culture (co-culture + mixed-cell organoids) to explore contact-dependent and independent interactions, (4) Use of in vivo experimental mouse models arthritis (ie the meBSA model).


References

KEY PUBLICATIONS:
1. Chang, M. H., Levescot, A., Nelson-Maney, N., Blaustein, R. B., Winden, K. D., Morris, A., Wactor, A., Balu, S., Grieshaber-Bouyer, R., Wei, K., Henderson, L. A., Iwakura, Y., Clark, R. A., Rao, D. A., Fuhlbrigge, R. C., & Nigrovic, P. A. (2021). Arthritis Flares Mediated by Tissue Resident Memory T Cells in the Joint. BioRxiv, 2021.06.04.446927. https://doi.org/10.1101/2021.06.04.446927
2. Miranda-Carús, M.-E., Balsa, A., Benito-Miguel, M., Pérez de Ayala, C., & Martín-Mola, E. (2004). IL-15 and the Initiation of Cell Contact-Dependent Synovial Fibroblast-T Lymphocyte Cross-Talk in Rheumatoid Arthritis: Effect of Methotrexate. The Journal of Immunology, 173(2). https://doi.org/10.4049/jimmunol.173.2.1463
3. Brown, F. D., Sen, D. R., LaFleur, M. W., Godec, J., Lukacs-Kornek, V., Schildberg, F. A., Kim, H.-J., Yates, K. B., Ricoult, S. J. H., Bi, K., Trombley, J. D., Kapoor, V. N., Stanley, I. A., Cremasco, V., Danial, N. N., Manning, B. D., Sharpe, A. H., Haining, W. N., & Turley, S. J. (2019). Fibroblastic reticular cells enhance T cell metabolism and survival via epigenetic remodeling. Nature Immunology 2019 20:12, 20(12), 1668–1680. https://doi.org/10.1038/s41590-019-0515-x
4. Macaubas, C., Nguyen, K., Milojevic, D., Park, J. L., & Mellins, E. D. (2009). Oligoarticular and polarticular JIA: epidemiology and pathogenesis. Nature Reviews. Rheumatology, 5(11), 616. https://doi.org/10.1038/NRRHEUM.2009.209
5. Friščić, J., Böttcher, M., Reinwald, C., Bruns, H., Wirth, B., Popp, S.-J., Walker, K. I., Ackermann, J. A., Chen, X., Turner, J., Zhu, H., Seyler, L., Euler, M., Kirchner, P., Krüger, R., Ekici, A. B., Major, T., Aust, O., Weidner, D., … Hoffmann, M. H. (2021). The complement system drives local inflammatory tissue priming by metabolic reprogramming of synovial fibroblasts. Immunity, 54(5), 1002-1021.e10. https://doi.org/10.1016/J.IMMUNI.2021.03.003
KEYWORDS: Inflammation, juvenile idiopathic arthritis, tissue-resident, genomics

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