EP001: The interferon transcriptome in uterine NK cells is upregulated during the second trimester of pregnancy allowing extravillous trophoblast invasion

Uterine Natural Killer (uNK) cells regulate essential developmental processes at the maternal-fetal interface during early pregnancy. Uterine NK cell functions are tightly regulated during early placentation to stimulate trophoblast invasion and remodel uterine spiral arteries. Access to human 1st and 2nd trimester uterine tissues allowed us to investigate the transcriptional changes in uNK cells during the early stages of early human pregnancy. Microarray analysis identified 97 upregulated genes in 2nd compared to 1st trimester purified uNK cells of which the majority (61%) clustered as interferon-stimulated-genes (ISG), with ISG15 and ISG20 being upregulated profoundly. Type I interferons (IFNα/β), but not type II interferon (IFNɣ) increased expression of the identified interferon target genes ISG15 and ISG20 in uNK cells in vitro. Moreover, the cytokine-like protein ISG15 stimulated in vitro trophoblast invasion. Second trimester uNK cells promoted trophoblast invasion in vitro, whereas both 1st and 2nd trimester uNK cells stimulated endothelial tube formation. IFNα but not IFNβ stimulation of 1st trimester uNK cells enhanced their capacity to promote trophoblast invasion. In conclusion, the uNK cell interferon transcriptome is upregulated during the 2nd trimester allowing uNK cells to promote trophoblast invasion. Type I interferon signaling regulates uNK cell-induced trophoblast invasion via induction of effector molecules like ISG15. First trimester uNK cells can be induced to act like second trimester uNK cells by IFNα with respect to promotion of trophoblast invasion. Key words: Gene expression profiling ■ uterine natural killer cells ■ extravillous trophoblast invasion ■ interferon alpha ■ ISG15 We performed microarray analysis on highly purified CD56brightCD16-CD3- uNK cells comparing decidual tissue from 1st and 2nd trimester pregnancy terminations. Each group consisted of 6 donors. Total RNA was amplified and labeled with cy5 and co-hybridized with cy3 labeled Stratagene Universal Reference RNA on Agilent human V2 arrays.