Continuous human uterine NK cell differentiation in response to endometrial regeneration and pregnancy just published in Science Immunology

24 February 2021

Benedikt Strunz1,Jonna Bister1, Hanna Jönsson1, Iva Filipovic1, Ylva Crona-Guterstam1,2,3, Egle Kvedaraite1,4, Natalie Sleiers1, Bogdan Dumitrescu5, Mats Brännström6, Antonio Lentini7, Björn Reinius7, Martin Cornillet1, Tim WillingeSebastian Gidlöf2,3,8, Russell S. Hamilton9,10, Martin A. Ivarsson1 and Niklas K. Björkström1,*

1Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
2Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Stockholm, Sweden.
3Department of Gynecology and Reproductive Medicine, Karolinska University Hospital Huddinge, Stockholm, Sweden.
4Childhood Cancer Research Unit, Department of Women’s and Children’s Health, Karolinska Institutet, Stockholm, Sweden.
5Department of Obstetrics and Gynecology, Mälarsjukhuset, Eskilstuna, Sweden.
6Department of Obstetrics and Gynecology, University of Gothenburg, Gothenburg, Sweden.
7Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
8Department of Obstetrics and Gynecology, Stockholm South General Hospital, Stockholm, Sweden.
9Centre for Trophoblast Research, University of Cambridge, Cambridge, UK
10Department of Genetics, University of Cambridge, Cambridge, UK.

*Corresponding author. Email: benedikt.strunz[at]ki.se (B.S.); niklas.bjorkstrom[at]ki.se (N.K.B.)

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.

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