Identification and characterisation of Group 3 Innate Lymphoid Cells in the renal tract

Innate lymphoid cells (ILCs) bear similarities to T-helper (Th) cells, but lack T cell receptors. The three groups mirror the effector functions of Th1, Th2 and Th17 cells and share the same transcription factors and cytokine profiles. This project focussed on type 3 ILCs (ILC3s) found primarily at mucosal surfaces with roles in immune defence, tolerance and homeostasis. The key aims were to identify ILC3s within the renal tract (bladder, ureter and kidneys) and characterise their role in urinary tract infection (UTI). UTI is a significant cause of morbidity and mortality, accounting for some cases of end stage renal failure. The commonest cause of uncomplicated UTI is Uropathogenic Escherichia coli and we used this organism in murine models to interrogate the role of ILC3s within this setting. The project focussed on three vital components of effective defence: the epithelium, mononuclear phagocytes (MNPs) and ILC3s. Key findings and conclusions Numbers of ILC3s and MNPs in the renal tract increased during UTI, as did their key products, interleukin 17 (IL-17a), IL-22 and granulocyte macrophage – colony stimulating factor (GM-CSF). By using Rag2 knockout mice (lacking T and B lymphocytes), we demonstrated that IL-17 was further decreased by ILC-depletion. Furthermore, we showed reciprocal loss of MNP recruitment, indicating pathways of ILC3-MNP crosstalk during UTI. Demonstrating a mechanism for ILC3 activation by MNPs through IL-23a and IL-1β production proved challenging, indicating the complexity of the system and requirements for co-stimulation. Similarly, mechanisms of IL-22-induced epithelial repair through production of antimicrobial peptides and induction of cell cycle genes proved multifactorial in origin, but carried particular importance within the bladder. This project also described ILC3s within the human renal tract by utilising tissues from transplant donors and genomic investigation of tissue-resident cells within the bladder was performed. This novel data will form an invaluable research resource.

Name dc:type.qualificationname

Doctor of Philosophy (PhD)

Level dc:type.qualificationlevel

Doctoral

Grantor dc:publisher.institution

University of Cambridge

Year dc:date.issued

2019

Author dc:creator

• Riding, Alexandra Mary

Advisor dc:contributor.advisor

• Clatworthy, Menna

• Innate lymphoid cells
• Urinary tract infection
• Bladder
• Renal tract
• Innate immunology

Licence

• https://apollo8-f-pro.lib.cam.ac.uk/bitstreams/b48a667f-f06c-4bf0-911c-5e6bf7775c61/download
• https://www.rioxx.net/licenses/all-rights-reserved/

Language dc:language

en

Author Identifier

0000-0002-6915-5671

OAI identifier oai:identifier

oai:www.repository.cam.ac.uk:1810/298094