Uncovering the role of IL-15 on uterine NK cells during the menstrual cycle
Year: 2025
Type: dissertation
Abstract: The endometrium, which is the inner mucosal lining of the uterus, is a dynamic tissue that responds to hormonal fluctuations during the menstrual cycle. In the endometrium, uterine natural killer cells (uNK) make up to 70 % of all lymphocytes. Besides immune defense, they are essential for interaction with extravillous trophoblast cells, to regulate placentation and implantation. Three uNK subtypes can be distinguished based on KIR and CD39 expression, with KIR+CD39+ uNK beeing the most differentiated. Fluctuations in the uNK phenotype during the menstrual cycle are connected to progesterone release after ovulation, that subsequently results in IL-15 secretion by stromal cells. IL-15, a critical cytokine for NK cell differentiation, has been found decreased in pregnancy complications and was linked to a shift in uNK subtypes. Here, the response of uNK cells to IL-15 was characterised by investigating the gene expression and early epigenetic regulation. Therefore, IL-15 naïve KIR-CD39- uNK cells and more differentiated KIR+CD39- derived from proliferative phase endometrial biopsies were FACS sorted and IL-15 stimulated. Following that, RNAseq and ATACseq was performed to analyse changes in transcription and chromatin accessibility, respectively. On gene expression level, IL-15 affected cellular characteristics and immune functions of both uNK subtypes. In less differentiated KIR- CD39- however, more target genes were found. Interestingly, expression of tissue residency marker, extracellular modelling proteins and granzymes showed increased expression in response to IL-15 stimulation. Pathway analysis suggested enrichment of differentially expressed genes for cell differentiation in KIR- CD39- uNK. Mechanistically, IL-15 stimulation leads to changes in chromatin accessibility for both uNK cell subtypes with motif enrichment for the STAT5 binding site in more accessible chromatin. First results for in-situ staining of phosphorylated STAT5, that is known to be part of the IL-15 pathway, confirmed increased signalling in later secretory compared to early proliferative phase endometrial tissue. To get a more complete picture during the cycle, the structure and cellular composition of menstrual phase endometrial tissue was described based on H&E staining as well as immunofluorescence staining. Isolation from mentrual blood is a way of non-invasive sampling and thereby this tissue has a high dignostic value. To conclude, this thesis contributes to the understanding of uNK cell characteristics on transcriptional, epigenetic and spatial level throughout the menstrual cycle.
Author: Fischer, Birte
Language: English
Subfield: Immunology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W7082419518