Continuous human uterine NK cell differentiation in response to endometrial regeneration and pregnancy

Abstract

Immune cell differentiation is critical for adequate tissue-specific immune responses to occur. Here, we studied differentiation of human uterine natural killer cells (uNK cells). These cells reside in a tissue undergoing constant regeneration and represent the major leukocyte population at the maternal-fetal interface. However, their physiological response during the menstrual cycle and in pregnancy remains elusive. By surface proteome and transcriptome analysis as well as using humanized mice, we identify a differentiation pathway of uNK cells in vitro and in vivo with sequential acquisition of killer cell immunoglobulin-like receptors and CD39. uNK cell differentiation occurred continuously in response to the endometrial regeneration and was driven by interleukin-15. Differentiated uNK cells displayed reduced proliferative capacity and immunomodulatory function including enhanced angiogenic capacity. By studying human uterus transplantation and monozygotic twins, we found that the uNK cell niche could be replenished from circulation and that it was under genetic control. Together, our study uncovers a continuous differentiation pathway of human NK cells in the uterus that is coupled to profound functional changes in response to local tissue regeneration and pregnancy.

Placenta-Derived Exosomes as a Modulator in Maternal Immune Tolerance During Pregnancy

“…Interestingly, endometrium exhibits a sharp increase in NK cells and macrophages and a steep decline in T cells during the secretory phase of menstrual cycle, indicating that hormones may influence immune cell population and functions. Although the total cell numbers of the decidual immune cells in the peri-implantation and post-implantation periods are similar, their phenotypes and functions are dramatically different ( 71 , 72 ).…”

How Do Uterine Natural Killer and Innate Lymphoid Cells Contribute to Successful Pregnancy?

“…These show both mechanisms contribute to increases in uNK at different times: tissue resident cells proliferate during early pregnancy in response to decidualization, while a second wave of recruitment of circulating NK cells augments uNK cell numbers in the second half of gestation ( 72 , 73 ). Recent data from HLA mismatched uterus transplant recipients in humans suggests that uNK can indeed be replenished from the circulation ( 74 ). This approach could be applied to establish whether other uILC subsets can also originate from the periphery and whether peripheral or tissue resident contributions vary during pregnancy, as seen in the mouse.…”

“…Recently, the ectonucleotidase, CD39, was found to be expressed by dNK1; this could combine with CD73 on EVT to convert ATP to adenosine, which is associated with local immune suppression ( 40 , 74 ). Trophoblast-specific T cells are likely to be HLA-C restricted, since this is the only polymorphic HLA-molecule on trophoblast.…”

“…ILC development in different tissues appears to have divergent pathways as demonstrated by the effects of Nfil3 deficiency on trNK and cNK subsets in the mouse uterus. Which subsets develop in situ and which arise from circulating precursors in the human uterus can be addressed by analysing uILCs from patients with bone marrow or uterine transplants with HLA-mismatched donors ( 74 , 144 ). ILCs also demonstrate considerable plasticity and the relationships between uNK subsets and other uILCs is unclear, although recent evidence suggests that dNK2 can convert to cells resembling dNK1 in vitro ( 76 ).…”

A Brief Analysis of Tissue-Resident NK Cells in Pregnancy and Endometrial Diseases: The Importance of Pharmacologic Modulation

“…They then were able to explore the most relevant miRNA in endometriosis [148][149][150]. This information is critical since directed therapies depending on endometriosis may provide new elements to control the inflammatory disease and aid in fertilization [148][149][150][151][152][153][154][155][156][157][158][159][160][161][162][163][164][165][166]. In addition, exosomes contain miRNA and other proteins.…”