These studies aimed to advance understanding of the functions of pregnancy-
associated uterine lymphocytes of the natural killer (NK) cell lineage. The
approach was morphometric analysis of implantation sites from timed pregna
ncies in genetically modified mice deficient in NK cells or in signaling as
sociated with their major product, the cytokine interferon-gamma. In four d
ifferent strains of pregnant, NK cell-deficient mice, the major decidual ar
terioles failed to undergo modifications to their smooth-muscle coats and d
isplayed endothelial cell damage. Decidua lacked normal cell density. This
pathology was observed by the end of the first trimester, before placental
differentiation. By midgestation in these strains, placentas were smaller t
han in control strains. In normal mice, many uterine NK cells are perivascu
lar in location and appear to be activated because they are the major sourc
es of interferon-gamma and of the interferon-gamma-regulated enzyme inducib
le nitric oxide synthase. During pregnancy in mice genetically ablated for
interferon-gamma, the interferon-gamma receptor chain-alpha or the transcri
ption factor interferon regulatory factor-1, uterine NK cells differentiate
but appear to be abnormal both morphologically and functionally. In these
three strains, failure of pregnancy-induced vascular modifications and over
t necrosis of decidua occur. Thus, in mice, lymphocytes of the NK cell line
age make specialized contributions to pregnancy-associated modification of
the uterine vasculature and to maintenance of decidua. These contributions
are achieved through interferon-gamma-mediated gene regulation and appear t
o enhance subsequent placental growth. Human CD56 bright decidual lymphocyt
es may have analogous functions. If so, changes in numbers or levels of act
ivity of human uterine NK cells or mutations in genes regulated by uterine
interferon-gamma could contribute to initiation of preeclampsia. Copyright
(C) 2000 by the Society for Gynecologic Investigations.