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

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.

You can view the full article here