Abstract
During pregnancy, a specialized type of NK cell accumulates in the lining of the uterus (decidua) and interacts with semiallogeneic fetal trophoblast cells. dNK cells are functionally and phenotypically distinct from PB NK and are implicated in regulation of trophoblast transformation of the uterine spiral arteries, which if inadequately performed, can result in pregnancy disorders. Here, we have used uterine artery Doppler RI in the first trimester of pregnancy as a proxy measure of the extent of transformation of the spiral arteries to identify pregnancies with a high RI, indicative of impaired spiral artery remodeling. We have used flow cytometry to examine dNK cells isolated from these pregnancies compared with those from pregnancies with a normal RI. We report a reduction in the proportion of dNK cells from high RI pregnancies expressing KIR2DL/S1,3,5 and LILRB1, receptors for HLA-C and HLA-G on trophoblast. Decreased LILRB1 expression in the decidua was examined by receptor blocking in trophoblast coculture and altered dNK expression of the cytokines CXCL10 and TNF-α, which regulate trophoblast behavior. These results indicate that dNK cells from high RI pregnancies may display altered interactions with trophoblast via decreased expression of HLA-binding cell-surface receptors, impacting on successful transformation of the uterus for pregnancy.
Highlights
Receptor repertoire of dNK cells isolated from high RI differs from dNK cells isolated from normal RI pregnancies dNK cells have been shown previously to express the following receptors: KIR2DL1/S1, KIR2DL2/S2, NKp30, NKp46, LILRB1, NKG2A, NKG2C, NKG2D, CD160, CD9, and CD69 [14, 15, 24, 25]
All receptors were expressed in the same proportion in high RI and normal RI pregnancies, with the exception of KIR2DL/S1,3,5 and LILRB1, which were expressed on a significantly lower proportion of dNK cells from high RI pregnancies (P, 0.05; Fig. 2)
DNKR repertoire varies with gestational age Percentages of dNK cells expressing receptors, including KIR2DL1/S1, LILRB1, and NKG2D, have been demonstrated to alter throughout the first trimester of pregnancy [26, 27]
Summary
During the first trimester of pregnancy, maternal NK cells accumulate in the lining of the pregnant uterus (decidua). dNK cells are functionally and phenotypically distinct from their PBThe online version of this paper, found at www.jleukbio.org, includes supplemental information.counterparts, and the role they play in pregnancy is still unknown; they are implicated in regulation of invasion of the semiallogeneic fetal placenta [1,2,3]. EVTs achieve this through a combination of induced apoptosis and de-differentiation of vascular cells [9,10,11], eventually replacing the vascular cells they have displaced [12] To accomplish this aim, EVT must avoid an adverse immune reaction by the dNK cells. The unique maternal-fetal immune interaction may be enhanced by the dissimilar phenotype of dNK cells to PB NK cells; dNK cells are predominantly CD56brightCD16–, noncytotoxic, and cytokine-secreting cells [1] They express a different repertoire of inhibitory and activatory receptors to PB NK cells, which includes higher expression of the KIRs KIR2DL1/ S1 and KIR2DL2/S2 [14]; the 3 NCRs NKp46, NKp30, and NKp44; and LILRB1 [15]
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