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Regulation of intestinal immune homeostasis and inflammation by the gut microbiota


Project Description

Our immune system must fight harmful pathogens, but remain silent against harmless substances such as the trillions of bacteria found in the gut that are beneficial for health. If our immune system attacks these bacteria (the “microbiota”), inflammatory bowel disease (IBD) can occur, which is a painful, debilitating condition affecting millions worldwide. Although the causes of IBD are poorly understood, there is mounting evidence that previous antibiotic use may be an important risk factor. However, why antibiotics increase IBD risk is currently unknown.

Work from the Mann lab has recently demonstrated that disruption of the gut microbiota with antibiotic use causes immune cells called T-cells to become over-active in the gut, resulting in long-lived inflammation, and that this enhanced T-cell activation is driven by changes in specialised immune cells called antigen-presenting cells (APCs). However, the specific mechanisms by which antibiotic use drives T-cell inflammation via APCs is still not clear. Such information is crucial in understanding how immune cells in the intestine are controlled to “ignore” the harmless bacteria and how this process breaks down in IBD to mediate pathology.

In this PhD project, using a multi-disciplinary approach combining in vivo mouse models of disease with directly relevant primary human immune cells, we will determine crucial pathways by which antibiotic use drives APC-dependent inflammation in the intestine. Specific focus will be on the important cytokine TGF, which has been shown in other systems to play important roles in regulation of intestinal T cell responses. This project will provide a unique training opportunity to combine immunology with TGF biology to identify crucial mechanisms that link antibiotic use to development of inflammation and IBD.

Training/techniques to be provided:
This project will involve analysis of regulatory versus inflammatory T cell responses in the intestine using mouse models of disease combined with human samples, using a variety of in vitro and in vivo immunological assays. Training in these techniques will be provided, including primary immune cell isolation and characterisation by flow cytometry, cell culture and cell stimulation assays, fluorescence-activated cell sorting, isolation of RNA for global gene expression analysis using RNAseq (outsourced) and looking at candidate gene function by CRISPR-mediated knockdown in primary intestinal cells. Thus, the student will be provided with a unique training opportunity combining in vivo intestinal immunology, cellular and molecular biology and translational medicine.

Funding Notes

Candidates are expected to hold (or be about to obtain) a minimum upper second class honours degree (or equivalent) in a related area / subject. Candidates with experience in biomedical sciences or with an interest in immunology are encouraged to apply.

This project has a Band 3 fee. Details of our different fee bands can be found on our website (View Website). For information on how to apply for this project, please visit the Faculty of Biology, Medicine and Health Doctoral Academy website (View Website).

Informal enquiries may be made directly to the primary supervisor.

References

Fenton TM, Kelly A, Shuttleworth EE, Smedley C, Atakilit A, Powrie F, Campbell S, Nishimura SL, Sheppard D, Levison S, Worthington JJ, Lehtinen MJ, Travis MA (2017). Inflammatory cues enhance TGFβ activation by distinct subsets of human intestinal dendritic cells via integrin αvβ8. Mucosal Immunology, 10:624-634.

Mann, E.R., Bernardo, D., English N.R., Landy, J., Al-Hassi, H.O., Peake, S.T.C., Man, R., Elliott, T., Spranger, H., Parian, A., Brant, S., Lazarev, M., Hart, A.L., Li, X. and Knight, S.C. (2016). Compartment-specific immunity in the human gut: properties and functions of dendritic cells in the colon versus the ileum. Gut. 65(2):256-70

Mann, E.R., Bernardo, D., Al-Hassi, H.O., Landy, J., Peake, S.T.C., Man, R., Han Lee, G., Yassin, N., Sarkar, S., Elliott, T., Thomas, L.V., Knight, S.C. and Hart, A.L. (2015). Human gut dendritic cells in ulcerative colitis drive aberrant, gut- specific T-cell responses characterised by increased IL-4 production and a loss of IL-22 and IFNγ. Inflammatory Bowel Diseases. 20(12): 2299-2307.

Worthington JJ, Kelly A, Smedley C, Bauché D, Campbell S, Marie JC, Travis MA (2015). Integrin αvβ8-mediated TGFβ activation by effector regulatory T-cells is essential for suppression of T-cell-mediated inflammation. Immunity, 42, 903-915.

Mann, E.R. and Li, X. Intestinal antigen-presenting cells in mucosal immune homeostasis: crosstalk between dendritic cells, macrophages and B-cells (2014). World Journal of Gastroenterology. 7;20(29):9653-64.

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