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Title: Molecular definition of group 1 innate lymphoid cells in the uterus
Author: Filipovic, Iva
ISNI:       0000 0004 7968 4301
Awarding Body: University of Cambridge
Current Institution: University of Cambridge
Date of Award: 2019
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Uterine NK cells (uNKs) are group 1 (g1) innate lymphoid cells (ILCs) that have been shown to regulate remodelling of uterine blood vessels, an event necessary to support fetal growth. Recently, other ILCs were identified in the mucosa and wall of the uterus of mice and women, pregnant or not. They may regulate important functions as they produce factors known to impact on uterine physiology and pathology. Unique to the mouse uterus is a population of CD49a+Eomes+ g1 ILCs (trNK), resembling human uNK cells. However, how they relate to uterine Eomes+CD49a- conventional NK cells (cNK) and CD49a+Eomes- ILC1 has been unknown. Determining the function of uterine lymphocytes is challenging because of the rapidly changing nature of the organ in response to sex hormones and, during pregnancy, to the invading fetal trophoblast cells. In my work, I provide the first genome- wide transcriptome atlas of mouse uterine g1 ILCs at mid-gestation. I show that the composition of g1 ILCs fluctuates throughout reproductive life, with CD49a+Eomes- ILC1s dominating before puberty and specifically expanding in second pregnancies, when the expression of CXCR6, a marker of memory NK cells, is upregulated. Tissue-resident CD49a+Eomes+ NK cells (trNK) are most abundant during early pregnancy, and showcase gene signatures of responsiveness to TGF-b. On the transcriptome level, they are also equipped with the machinery that may allow them to interact with majority of other cells at the maternal-fetal interface, as well as with the extracellular matrix. Conventional NK cells expand late in gestation and may interact with trNK cells through the production of IL-18 and IFN-g. These results identify trNK cells as the cellular hub of uterine g1 ILCs at mid- gestation and mark CXCR6+ ILC1s as potential memory cells of pregnancy. I have also identified in the uterus an early developmental stage along the g1 ILC lineage. The identification of this stage of lymphoid development should facilitate the delineation of g1 ILC differentiation in the uterus. This study represents the first report of the uterine g1 ILC transcriptome and it will be an essential resource for designing future studies in the field of reproductive immunology. Determining the molecular identity and function of mouse uterine g1 ILCs as demonstrated here will be instrumental to guide further work with human uNKs.
Supervisor: Burton, Graham ; Colucci, Francesco Sponsor: Centre for Trophoblast Research
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
Keywords: immunology ; reproduction ; natural killer cells