Trained Memory of Human Uterine NK Cells Enhances Their Function in Subsequent Pregnancies

Area of Science:

• Reproductive immunology
• Maternal-fetal interface immunology

Background:

• Natural killer cells (NKs) in the human decidua play crucial roles in regulating trophoblast invasion and angiogenesis.
• Poor placental development, often seen in first pregnancies, suggests potential differences in decidual NK cells (dNKs) between first and subsequent pregnancies.

Purpose of the Study:

• To characterize differences in decidual NK cells (dNKs) between first and repeated pregnancies.
• To identify and define a novel dNK cell population associated with repeated pregnancies.

Main Methods:

• Transcriptome and epigenetic profiling of dNKs from women with first versus repeated pregnancies.
• Analysis of receptor expression (NKG2C, LILRB1) and gene enhancer activity (IFNG, VEGFA).
• Functional assays assessing IFN-γ and VEGFα production upon PTdNK activation.

Main Results:

• A distinct population of dNKs, termed Pregnancy Trained decidual NK cells (PTdNKs), was identified in repeated pregnancies.
• PTdNKs exhibit a unique transcriptome and epigenetic signature, with open chromatin near IFNG and VEGFA enhancers.
• Activated PTdNKs demonstrated increased secretion of IFN-γ and VEGFα, promoting vascular sprouting.

Conclusions:

• PTdNKs, characterized by NKG2C and LILRB1 expression, are primarily found in repeated pregnancies.
• The enhanced production of IFN-γ and VEGFα by PTdNKs suggests a role in supporting proper placentation.
• Precursors of PTdNKs may reside in the endometrium, highlighting a potential mechanism for improved placental development in subsequent pregnancies.