Uterine NK cells: Active regulators at the maternal-fetal interface

The Journal of clinical investigation (Impact Factor: 13.22). 05/2014; 124(5):1872-1879. DOI: 10.1172/JCI68107
Source: PubMed


Pregnancy presents an immunological conundrum because two genetically different individuals coexist. The maternal lymphocytes at the uterine maternal-fetal interface that can recognize mismatched placental cells are T cells and abundant distinctive uterine NK (uNK) cells. Multiple mechanisms exist that avoid damaging T cell responses to the fetus, whereas activation of uNK cells is probably physiological. Indeed, genetic epidemiological data suggest that the variability of NK cell receptors and their MHC ligands define pregnancy success; however, exactly how uNK cells function in normal and pathological pregnancy is still unclear, and any therapies aimed at suppressing NK cells must be viewed with caution. Allorecognition of fetal placental cells by uNK cells is emerging as the key maternal-fetal immune mechanism that regulates placentation.

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Available from: Francesco Colucci, Dec 11, 2014
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    • "The selective expression of p110d in leukocytes has made it an attractive pharmacological target to treat hematological malignancies and reduce unwanted immune responses in the context Cell Reports 13, 2817–2828, December 29, 2015 ª2015 The Authors 2817 of autoimmunity and allergy (Rodon et al., 2013). Maternal immune adaptations during pregnancy are instrumental for the development of the growing fetus (Erlebacher, 2013; Moffett and Colucci, 2014). We used transgenic knockin mice carrying a kinase-dead point mutation in the gene coding for p110d (d D910A ) as a genetic model for inactivation of the p110d pathway in order to investigate the effects of unbalanced maternal immune responses during gestation. "
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    ABSTRACT: Maternal immune cells are an integral part of reproduction, but how they might cause pregnancy complications remains elusive. Macrophages and their dual function in inflammation and tissue repair are thought to play key yet undefined roles. Altered perinatal growth underpins adult morbidity, and natural killer (NK) cells may sustain fetal growth by establishing the placental blood supply. Using a mouse model of genetic inactivation of PI3K p110δ, a key intracellular signaling molecule in leukocytes, we show that p110δ regulates macrophage dynamics and NK-cell-mediated arterial remodeling. The uterus of dams with inactive p110δ had decreased IFN-γ and MHC class II(low) macrophages but enhanced IL-6. Poor vascular remodeling and a pro-inflammatory uterine milieu resulted in fetal death or growth retardation. Our results provide one mechanism that explains how imbalanced adaptations of maternal innate immune cells to gestation affect offspring well-being with consequence perinatally and possibly into adulthood.
    Full-text · Article · Dec 2015 · Cell Reports
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    • "In some organs, NKcells exhibit specific phenotypes and functions [17] [18], for example, promoting decidualization of the endometrium, embryo implantation and placenta development [19] [20], and influencing the hematopoiesis [21] [22]. "
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    ABSTRACT: Studies of chemokine receptors (CKR) in natural killer- (NK-) cells have already been published, but only a few gave detailed information on its differential expression on blood NK-cell subsets. We report on the expression of the inflammatory and homeostatic CKR on normal blood CD56 + low CD16 + and CD56 + high CD16 - / + low NK-cells. Conventional CD56 + low and CD56 + high NK-cells present in the normal PB do express CKR for inflammatory cytokines, although with different patterns CD56 + low NK-cells are mainly CXCR1/CXCR2 + and CXCR3/CCR5 −/+ , whereas mostly CD56 + high NK-cells are CXCR1/CXCR2 − and CXCR3/CCR5 + . Both NK-cell subsets have variable CXCR4 expression and are CCR4 − and CCR6 − . The CKR repertoire of the CD56 + low NK-cells approaches to that of neutrophils, whereas the CKR repertoire of the CD56 + high NK-cells mimics that of Th1 + T cells, suggesting that these cells are prepared to migrate into inflamed tissues at different phases of the immune response. In addition, we describe a subpopulation of NK-cells with intermediate levels of CD56 expression, which we named CD56 + int NK-cells. These NK-cells are CXCR3/CCR5 + , they have intermediate levels of expression of CD16, CD62L, CD94, and CD122, and they are CD57 − and CD158a − . In view of their phenotypic features, we hypothesize that they correspond to a transitional stage, between the well-known CD56 + high and CD56 + low NK-cells populations.
    Full-text · Article · Oct 2015 · Journal of Immunology Research
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    • "23 [18–37] ns Systolic blood pressure (mmHg) 12 [10] [11] [12] [13] 14 [10] [11] [12] [13] [14] [15] [16] [17] [18] [19] [20] [21] [22] 12 [10] [11] [12] [13] í µí±ƒ < 0.001 * Diastolic blood pressure (mmHg) 7 [5–8.3] 8.7 [6] [7] [8] [9] [10] [11] [12] 7 [5.5–8.5] í µí±ƒ < 0.001 * Uterine height (cm) 32 [29] [30] [31] [32] [33] [34] [35] [36] [37] [38] 26 [15–36] 26 [15–36] í µí±ƒ < 0.001 § Term at sampling (weeks of gestation) 31.7 [15.3–41] 30 [17–41] 30 [17–41] ns Term at delivery (weeks of gestation) 40.3 [35] [36] [37] [38] [39] [40] [41] [42] 32.3 [17–41.1] "
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    ABSTRACT: The major histocompatibility complex class I related chain (MIC) is a stress-inducible protein modulating the function of immune natural killer (NK) cells, a major leukocyte subset involved in proper trophoblast invasion and spiral artery remodeling. Aim of the study was to evaluate whether upregulation of soluble MIC (sMIC) may reflect immune disorders associated to vascular pregnancy diseases (VPD). sMIC was more frequently detected in the plasma of women with a diagnostic of VPD (32%) than in normal term-matched pregnancies (1.6%, P < 0.0001), with highest prevalence in intrauterine fetal death (IUDF, 44%) and vascular intrauterine growth restriction (IUGR, 39%). sMIC levels were higher in preeclampsia (PE) than in IUFD (P < 0.01) and vascular IUGR (P < 0.05). sMIC detection was associated with bilateral early diastolic uterine notches (P = 0.037), thrombocytopenia (P = 0.03), and high proteinuria (P = 0.03) in PE and with the vascular etiology of IUGR (P = 0.0038). Incubation of sMIC-positive PE plasma resulted in downregulation of NKG2D expression and NK cell-mediated IFN-γ production in vitro. Our work thus suggests that detection of sMIC molecule in maternal plasma may constitute a hallmark of altered maternal immune functions that contributes to vascular disorders that complicate pregnancy, notably by impairing NK-cell mediated production of IFN-γ, an essential cytokine favoring vascular modeling.
    Full-text · Article · Aug 2014 · BioMed Research International
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