Natural Killer cells in early pregnancy

Abstract

Uterine NK cells (uNK) are the most numerous immune cells found in the uterine mucosa at the time of implantation, during mid-secretory phase of the menstrual cycle and in early pregnancy. They are thought to facilitate extravillous trophoblast (EVT) invasion and vascular remodelling during placentation. It has been recently discovered that uNK are comprised of three subsets in first trimester decidua which are postulated to have different roles in pregnancy. Here, I have used flow cytometry to interrogate the frequency, phenotype and function of uNK subsets through the human reproductive cycle. My findings showed that uNK1 and uNK2 peak in first trimester, but all three subsets upregulate KIR and LILRB1 receptors which interact with HLA-C and HLA-G on EVT cells respectively. Moreover, all three uNK subsets displayed highest ability to degranulate and produce IL-8, TNF-α and IFN-γ during the secretory phase. My systematic review on women with recurrent miscarriage (RM) and implantation failure (RIF) showed that total CD56+ cells in the uterus is significantly raised in the endometrium, but not in the decidua after miscarriage. I proceeded to assess uNK subsets in mid-luteal endometrium of women with unexplained infertility, RM and RIF. My findings suggest that reproductive failure is associated with global reduction of KIR and LILRB1 uNK receptors, reduced uNK activation and disrupted uNK cytokine production. In order to assess the efficacy of immunotherapy in RM and RIF patients with raised NK cells, I conducted another systematic review and concluded there is insufficient high-quality evidence to justify immunotherapy in RM and RIF patients with raised NK cells. Finally, I assessed circulating NK cells and NK progenitors to determine mechanism of recruitment for uNK. Although I was unable to make firm conclusion on which cell is being recruited, there are some suggestive trends on which chemokine receptors are involved. Taken together, my findings will inform greater focus on aspects of phenotype and function of uNK subsets in future research.