Research ArticleNK CELLS

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

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Science Immunology  19 Feb 2021:
Vol. 6, Issue 56, eabb7800
DOI: 10.1126/sciimmunol.abb7800

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NK cells ride the uterine cycle

Tissue-resident natural killer (NK) cells in the uterus promote successful pregnancies by regulating the depth of placental trophoblast invasion. Endometrial tissue is naturally subject to constant remodeling in response to hormonal fluctuations during the menstrual cycle, but how the changing uterine microenvironment influences the heterogeneity of uterine NK (uNK) cells is poorly understood. Strunz et al. used proteomic and transcriptomic techniques to profile human uNK cells recovered from different stages of the menstrual cycle and during pregnancy. This analysis identified sequentially expressed uNK cell surface markers that define a recurring cycle of differentiation in response to progesterone-regulated release of stromal IL-15. These findings pave the way for further studies on how uNK cell functions are modulated by the dynamic endometrial microenvironment.


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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