ILC3 dynamics at the human uterine mucosal interface – a focus on IL-22
File(s)
Author(s)
Cuff, Antonia Olivia
Type
Thesis or dissertation
Abstract
Type 3 innate lymphoid cells (ILC3) preserve mucosal epithelial integrity during bacterial infection by secreting molecules such as IL-22. In the mouse, evidence suggests IL-22 functions at the uterine mucosal interface to protect against infection-induced preterm birth. IL-22-producing ILC3 were described in the human uterus and serum IL-22 decreases in the blood of women entering labour at term, potentially indicating a requirement for ILC3, and thus also IL-22, in maintaining a healthy pregnancy. Accordingly, this thesis began by investigating a potential role for uterine ILC3 in infectious and physiological labour. This required that I first define the number and function of uterine ILC3 in the normal reproductive cycle.
Strikingly, uterine ILC3 were most numerous and functional outside of pregnancy, potentially implicating them in reproductive function beyond pregnancy and parturition. I describe novel CD127– ILC3 which resembled conventional uterine ILC3. I found that endothelial, stromal, and epithelial cells respond to ILC3 products, based on their expression of the IL-22 receptor, and the receptor for another ILC3 product, IL-8. I further show that these cells modulate their responsiveness to IL-22 or IL-8 at different reproductive stages by changing IL-22 and IL-8 receptor expression. In several pregnancy samples collected from patients with infectious aetiologies, ILC3 frequency and number did not differ from uninfected controls, but they produced more IL-22 and IL-8 in specific uterine compartments. A potential role for ILC3 in the gynaecological pathology, endometriosis, was also investigated however, no clear differences in ILC3 numbers or function were identified although ILC3 were located further from blood vessels and glands.
Ultimately, I provide the first detailed description of uterine ILC3 dynamics in the healthy reproductive cycle. This information can be leveraged to understand how ILC3 contribute to uterine pathologies and how they uniquely modulate processes at the uterine mucosal interface, distinct from other ILC.
Strikingly, uterine ILC3 were most numerous and functional outside of pregnancy, potentially implicating them in reproductive function beyond pregnancy and parturition. I describe novel CD127– ILC3 which resembled conventional uterine ILC3. I found that endothelial, stromal, and epithelial cells respond to ILC3 products, based on their expression of the IL-22 receptor, and the receptor for another ILC3 product, IL-8. I further show that these cells modulate their responsiveness to IL-22 or IL-8 at different reproductive stages by changing IL-22 and IL-8 receptor expression. In several pregnancy samples collected from patients with infectious aetiologies, ILC3 frequency and number did not differ from uninfected controls, but they produced more IL-22 and IL-8 in specific uterine compartments. A potential role for ILC3 in the gynaecological pathology, endometriosis, was also investigated however, no clear differences in ILC3 numbers or function were identified although ILC3 were located further from blood vessels and glands.
Ultimately, I provide the first detailed description of uterine ILC3 dynamics in the healthy reproductive cycle. This information can be leveraged to understand how ILC3 contribute to uterine pathologies and how they uniquely modulate processes at the uterine mucosal interface, distinct from other ILC.
Version
Open Access
Date Issued
2023-08
Date Awarded
2024-03
Copyright Statement
Creative Commons Attribution NonCommercial Licence
Advisor
Male, Victoria
MacIntyre, David
Sponsor
Borne (Charity)
Publisher Department
Department of Metabolism, Digestion and Reproduction
Publisher Institution
Imperial College London
Qualification Level
Doctoral
Qualification Name
Doctor of Philosophy (PhD)