期刊
SCIENCE IMMUNOLOGY
卷 6, 期 56, 页码 -出版社
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/sciimmunol.abb7800
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资金
- Swedish Research Council
- Swedish Cancer Society
- Swedish Foundation for Strategic Research
- Cancer Research Foundations of Radiumhemmet
- Knut and Alice Wallenberg Foundation
- Novo Nordisk Foundation
- Center for Innovative Medicine at Karolinska Institutet
- Region Stockholm
- SRP Diabetes Karolinska Institutet
- StratRegen Karolinska Institutet
- Karolinska Institutet
- Wenner-Gren Foundations
The study reveals a continuous differentiation pathway of human uterine natural killer cells coupled with profound functional changes in response to local tissue regeneration and pregnancy.
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.
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