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Regulation of intestinal immune responses to commensal bacteria by innate lymphoid cells


Project Description

Commensal bacteria present in the gastrointestinal tract provide beneficial roles for the host, such as supporting nutrient metabolism. In order to peacefully co-exist with the intestinal microflora the immune system has evolved multiple mechanisms through which it suppresses inflammatory immune responses against these mutualistic microorganisms, which together generate a tolerogenic environment. A breakdown in this tolerance can result in the onset of chronic inflammatory disorders such as Inflammatory Bowel Disease (and colon cancer), hepatitis, and rheumatoid arthritis.

Innate lymphoid cells (ILCs) play key roles in mediating intestinal immune homeostasis and maintaining healthy host-commensal bacteria interactions via the production of cytokines, interactions with other tissue-resident immune cell populations and the orchestration of local immune responses (reviewed in Sonnenberg and Hepworth, Nature Reviews Immunology 2019). In particular, recent studies have demonstrated that group 3 innate lymphoid cells (ILC3) are able to prevent intestinal inflammation by controlling the activation of commensal bacteria-specific inflammatory T cells in an antigen-specific manner (Hepworth et al Nature 2013, Science 2015). Moreover, we recently demonstrate that ILC3 also regulate secretory Immunoglobulin (Ig)A production in order to control commensal bacterial colonization within the gut (Melo-Gonzalez et al, J Exp Med 2019).

This project will investigate i) how ILCs interact with intestinal immune cells to regulate responses to commensal bacteria ii) which bacterial species preferentially drive intestinal inflammation following disruption of ILC regulatory function(s) and iii) the specificity of ILC-regulation of inflammatory responses.

The project will utilize a range of approaches including the use of animal models, immunological techniques (flow cytometry, ELISA), molecular biology (PCR, sequencing) and microbiological methods to investigate interactions between the host immune system and the commensal microbiota in the context of health and disease. The student will my join my laboratory located within the world-class Faculty of Biology, Medicine and Health (FBMH) and Lydia Becker Institute of Immunology and Inflammation at the University of Manchester and will have access to a wide range of facilities and expertise across the faculty.

Training/techniques to be provided:
- In vivo models of disease and immune function
- Basic Immunological techniques (Flow Cytometry, ELISA)
- Basic microbiological techniques (16S PCR, culturing and infections with bacterial species, germ free mice)
- Basic molecular biology techniques (RT-PCR, potential for RNA sequencing and/or genomics approaches)

Entry Requirements:
The candidate will be expected to hold an upper second class or first class honours degree in a relevant or related subject (e.g. Immunology, microbiology, biomedical sciences). Preferably candidates will also hold a Masters level degree or equivalent and be able to demonstrate research laboratory experience and exposure to basic research in the field or in a related field, and some prior competence in basic laboratory techniques (e.g. cell culture, PCR).

For international students we also offer a unique 4 year PhD programme that gives you the opportunity to undertake an accredited Teaching Certificate whilst carrying out an independent research project across a range of biological, medical and health sciences. For more information please visit http://www.internationalphd.manchester.ac.uk

Funding Notes

Applications are invited from self-funded students. 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).

As an equal opportunities institution we welcome applicants from all sections of the community regardless of gender, ethnicity, disability, sexual orientation and transgender status. All appointments are made on merit.

References

1. Sonnenberg G.F. and Hepworth M.R.
Functional interactions between innate lymphoid cells and the adaptive immune system
Nature Reviews Immunology (2019)

2. Melo-Gonzalez F, Kammoun H, Evren E, Papdopoulou M, Bradford B, Mabbott N, Tanes C, Fardus-Reid F, Swann J.R., Bittinger K, Vallance B, Withers D.R., Willinger T, Hepworth M.R.
Antigen presenting ILC3 regulate T cell-dependent IgA responses to colonic bacteria
J Exp Med (2019)

3. Withers D.R., Hepworth M.R., Wang X, Mackley E.C., Halford E.E., Dutton E.E., Marriot C.L., Brucklader-Waldert V, Veldhoen M, Elson C.O., Kelsen J, Baldassano R.N., Sonnenberg G.F.
Transient inhibition of RORt differentially influences innate versus adaptive immunity to therapeutically limit intestinal inflammation.
Nature Medicine (2016)

4. Hepworth M.R., Fung T.C., Masur S.H., Kelsen J.R., MacConnell F.M., Dubrot J, Withers D.R., Hugues S, Farrar M.A., Reith W, Eberl G, Baldassano R.N., Laufer T.M., Elson C.O., Sonnenberg G.F.
Group 3 innate lymphoid cells mediate intestinal selection of commensal bacteria-specific CD4+ T cells
Science (2015)

5. Hepworth M.R., Monticelli L.A., Fung T.C., Ziegler C.G., Grunberg S, Sinha R, Mategazza A.R., Ma H.L., Crawford A, Angelosanto J.M., Wherry E.J., Koni P.A., Bushman F.D., Elson C.O., Eberl G, Artis D, Sonnenberg G.F.
Innate lymphoid cells regulate CD4+ T cell responses to commensal bacteria
Nature (2013)

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