Decidual NK cells (dNK) are the most abundant maternal leukocytes in the decidua, especially in the first trimester, making up 70% of the maternal CD45+ leukocyte population. (48) The dNK cells are distinct from majority of peripheral blood NK cells, in that they are large, granular, and are CD56hi and CD16− (8). The origin of these cells is unclear, although some have proposed possible recruitment of a subset of peripheral blood CD56hi NK cells into the decidua (49). Interestingly, during early pregnancy, dNK accumulate as a dense infiltrate around the trophoblast cells, but they progressively decrease in number from mid-gestation onward (50). This timing seems to implicate that dNK cells may be involved in modulating trophoblast invasion and vascular remodeling. Indeed, dNK have been shown to produce vascular endothelial growth factor C (VEGFC), placental growth factor (PIGF), and angiopoietin 2 (ANG2).
Decidual NK cells may also be important in modulating the degree of trophoblast invasion, as they are seen in close proximity to the invading trophoblasts in the decidua. Certainly, dNK have been shown to express killer inhibitory receptor (KIR) (51), CD94/NKG2A (52), and ILT2 (53), which recognize HLA-C and HLA-G, respectively, expressed on trophoblast cells. The HLA-C–KIR interaction is thought to be important in the pathogenesis of pre-eclampsia. As HLA-C is dimorphic and KIR polymorphic, it has been shown that certain combinations of maternal KIR and fetal HLA-C lead to an increased risk of pre-eclampsia, possibly through modulation of trophoblast migration, implying that HLA-C–KIR interaction is important in placentation (54, 55). However, NK cell KIR and HLA-C mismatch clearly does not explain all cases of pre-eclampsia, since only 30% of pre-eclamptic pregnancies have the at-risk maternal KIR phenotype (KIR AA) (54). HLA-G–ILT2 interaction on NK cells on the other hand, has been shown to increase dNK secretion of inflammatory and proangiogenic factors such as IL-1β, IL-6, TNF, and IL-8 (56). NK cells themselves are also susceptible to modulation by the decidual cytokine milieu. Indeed, dNK cells are thought to be the mediator of fetal demise in IL-10-deficient mice treated with LPS, which conversely can be rescued by administration of IL-10 (57). This suggests that IL-10 may modulate dNK cell cytotoxicity.
Collectively, these data suggest that dNK cells are important for modulation of trophoblast invasion and decidual vascularization in pregnancy. However, the recognition and tolerance of paternal allo-antigens via APC presentation during pregnancy, clearly requires the participation of other limbs of the immune system, such as the adaptive immune cells.
Decidual NK cells (dNK) are the most abundant maternal leukocytes in the decidua, especially in the first trimester, making up 70% of the maternal CD45+ leukocyte population. (48) The dNK cells are distinct from majority of peripheral blood NK cells, in that they are large, granular, and are CD56hi and CD16− (8). The origin of these cells is unclear, although some have proposed possible recruitment of a subset of peripheral blood CD56hi NK cells into the decidua (49). Interestingly, during early pregnancy, dNK accumulate as a dense infiltrate around the trophoblast cells, but they progressively decrease in number from mid-gestation onward (50). This timing seems to implicate that dNK cells may be involved in modulating trophoblast invasion and vascular remodeling. Indeed, dNK have been shown to produce vascular endothelial growth factor C (VEGFC), placental growth factor (PIGF), and angiopoietin 2 (ANG2).Decidual NK cells may also be important in modulating the degree of trophoblast invasion, as they are seen in close proximity to the invading trophoblasts in the decidua. Certainly, dNK have been shown to express killer inhibitory receptor (KIR) (51), CD94/NKG2A (52), and ILT2 (53), which recognize HLA-C and HLA-G, respectively, expressed on trophoblast cells. The HLA-C–KIR interaction is thought to be important in the pathogenesis of pre-eclampsia. As HLA-C is dimorphic and KIR polymorphic, it has been shown that certain combinations of maternal KIR and fetal HLA-C lead to an increased risk of pre-eclampsia, possibly through modulation of trophoblast migration, implying that HLA-C–KIR interaction is important in placentation (54, 55). However, NK cell KIR and HLA-C mismatch clearly does not explain all cases of pre-eclampsia, since only 30% of pre-eclamptic pregnancies have the at-risk maternal KIR phenotype (KIR AA) (54). HLA-G–ILT2 interaction on NK cells on the other hand, has been shown to increase dNK secretion of inflammatory and proangiogenic factors such as IL-1β, IL-6, TNF, and IL-8 (56). NK cells themselves are also susceptible to modulation by the decidual cytokine milieu. Indeed, dNK cells are thought to be the mediator of fetal demise in IL-10-deficient mice treated with LPS, which conversely can be rescued by administration of IL-10 (57). This suggests that IL-10 may modulate dNK cell cytotoxicity.Collectively, these data suggest that dNK cells are important for modulation of trophoblast invasion and decidual vascularization in pregnancy. However, the recognition and tolerance of paternal allo-antigens via APC presentation during pregnancy, clearly requires the participation of other limbs of the immune system, such as the adaptive immune cells.
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