About the Project
The incidence and prevalence of Inflammatory bowel disease (IBD), both ulcerative colitis and Crohn’s disease, is increasing globally[1] and presents as a comorbidity in a number of autoimmune conditions, including liver autoimmunities, especially Primary Sclerosing Cholangitis (PSC) and the inflammatory joint condition, rheumatoid arthritis. Improved management of these conditions requires improved understanding of the pathological mechanisms that underlie IBD.
CD4(+) T cells expressing the transcription factor FoxP3 have a non-redundant suppressive role in the control of excessive immune responses. Reduced numbers of these so-called regulatory T cells (Treg) have been found in the blood and colon of IBD patients [2] while others including our lab have found impaired function of Treg cells but increased numbers (3,4,5), implying a role for Treg instability in its pathology. In recent years, several transcription factors in addition to FoxP3 have been identified that might be important in the stability and function of Tregs[6, 7]. Amongst these are members of the Ikaros family of zinc-finger transcription factors, including Eos, Helios and Aiolos, wherein Eos appears to mediate FoxP3-dependent gene silencing whilst Aiolos is associated with Th17 differentiation and the potential loss of Treg stability[7].
A recent systems biologic analysis of Treg genetic pathways in a murine model of Primary Biliary Cholangitis (PBC) indicates Eos down regulation in this condition[8]. Restoring Eos expression and restricting the generation of Aiolos+ Tregs might therefore hold promise in the treatment of IBD and its comorbidities. However, conditions, which regulate the expression of these transcription factors and their relevance in the plasticity of human regulatory and helper T cell subsets, are currently poorly understood. This project therefore aims to identify factors that regulate Ikaros family transcription factors in human immune cell populations, the influence of their regulation upon T cell function and their relevance in IBD and autoimmune liver disease pathologies.
The project will make use of state of the art equipment for high density immunophenotyping including flow cytometry, mass cytometry (CyTOF) and fluorescence microscopy as well as DNA sequencing technologies. Most of the work will be conducted within the institute of Immunology and Immunotherapy that is situated in the Institute of Biomedical Research (IBR) Building, where the successful student will become an important member of a dedicated team of postdoctoral researchers and clinical research fellows from whom they will receive training and support. This translational project also benefits from close physical access to regular specialist IBD and liver disease clinics at the Queen Elizabeth Hospital and association with the Institute of Translational Medicine.
Person Specification
Applicants should have a strong background in cell biology, and ideally a background in Immunology. They should have a commitment to research in Medical sciences and hold or realistically expect to obtain at least an Upper Second Class Honours Degree in Molecular Cell biology or a relevant subject.
How to apply
Informal enquiries should be directed to Prof Subrata Ghosh ([Email Address Removed]) or Dr Louisa Jeffery ([Email Address Removed])
Applications should be directed to Libbi Coldicott (email: [Email Address Removed]). To apply, please send:
• A detailed CV, including your nationality and country of birth;
• Names and addresses of two referees;
• A covering letter highlighting your research experience/capabilities;
• Copies of your degree certificates with transcripts;
• Evidence of your proficiency in the English language, if applicable.
References
1 Molodecky, N. A., Soon, I. S., Rabi, D. M., Ghali, W. A., Ferris, M., Chernoff, G., Benchimol, E. I., Panaccione, R., Ghosh, S., Barkema, H. W. and Kaplan, G. G., Increasing incidence and prevalence of the inflammatory bowel diseases with time, based on systematic review. Gastroenterology 2012. 142: 46-54 e42; quiz e30.
2 Boden, E. K. and Snapper, S. B., Regulatory T cells in inflammatory bowel disease. Curr Opin Gastroenterol 2008. 24: 733-741.
3 Hirota SA, Ueno A, Tulk SE, Becker HM, Schenck LP, Potentier MS, Li Y, Ghosh S, Muruve DA, MacDonald JA, Beck PL. Exaggerated IL-15 and Altered Expression of foxp3+ Cell-Derived Cytokines Contribute to Enhanced Colitis in Nlrp3-/- Mice. Mediators Inflamm. 2016;2016:5637685.
4 Ueno A, Jijon H, Chan R, Ford K, Hirota C, Kaplan GG, Beck PL, Iacucci M, Fort Gasia M, Barkema HW, Panaccione R, Ghosh S. Increased prevalence of circulating novel IL-17 secreting Foxp3 expressing CD4+ T cells and defective suppressive function of circulating Foxp3+ regulatory cells support plasticity between Th17 and regulatory T cells in inflammatory bowel disease patients. Inflamm Bowel Dis. 2013 Nov;19(12):2522-34.
5. Li J, Ueno A, Fort Gasia M, Luider J, Wang T, Hirota C, Jijon HB, Deane M, Tom M, Chan R, Barkema HW, Beck PL, Kaplan GG, Panaccione R, Qian J, Iacucci M, Gui X, Ghosh S. Profiles of Lamina Propria T Helper Cell Subsets Discriminate Between Ulcerative Colitis and Crohn's Disease. Inflamm Bowel Dis. 2016 Aug;22(8):1779-92.
6 Fu, W., Ergun, A., Lu, T., Hill, J. A., Haxhinasto, S., Fassett, M. S., Gazit, R., Adoro, S., Glimcher, L., Chan, S., Kastner, P., Rossi, D., Collins, J. J., Mathis, D. and Benoist, C., A multiply redundant genetic switch 'locks in' the transcriptional signature of regulatory T cells. Nat Immunol 2012. 13: 972-980.
7 Raffin, C., Pignon, P., Celse, C., Debien, E., Valmori, D. and Ayyoub, M., Human memory Helios- FOXP3+ regulatory T cells (Tregs) encompass induced Tregs that express Aiolos and respond to IL-1beta by downregulating their suppressor functions. J Immunol 2013. 191: 4619-4627.
8 Wang, Y. H., Yang, W., Yang, J. B., Jia, Y. J., Tang, W., Gershwin, M. E., Ridgway, W. M. and Lian, Z. X., Systems biologic analysis of T regulatory cells genetic pathways in murine primary biliary cirrhosis. J Autoimmun 2015. 59: 26-37.
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