Maternal T Cells in the Human Placental Villi Support an Allograft Response during Noninfectious Villitis

Enninga, Elizabeth Ann L.; Raber, Patrick; Quinton, Reade A.; Ruano, Rodrigo; Ikumi, Nadia M.; Gray, Clive M.; Johnson, Erica L.; Chakraborty, Rana; Kerr, Sarah E.

doi:10.4049/jimmunol.1901297

Cited by 24 publications

(19 citation statements)

References 58 publications

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“…Villitis of unknown etiology (VUE) is a type of intrauterine inflammation and destructive inflammatory lesion resulting in placental destruction and dysfunction, which is characterized by the infiltration of maternal T cells-especially cytotoxic CD8+ T cellsinto the placenta, specifically into the chorionic villi (fetal tissue) (1). VUE is a crucial cause of preeclampsia, intrauterine growth restriction, small-for-gestational-age fetuses, fetal/neonatal death, spontaneous preterm delivery and recurrent reproductive loss, and neonatal neurocognitive impairment (2)(3)(4)(5). VUE is also believed to destruct large fetal vessels in the placenta leading to obliterative fetal vasculopathy, which is a high-risk factor for neonatal encephalopathy and cerebral palsy (6,7).…”

Section: Introductionmentioning

confidence: 99%

Type 1 Cytotoxic T Cells Increase in Placenta after Intrauterine Inflammation

Liu

Panda

et al. 2021

Front. Immunol.

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CD8+ T cells recognize non-self antigen by MHC class I molecules and kill the target cells by the release of proinflammatory cytokines such as interferon gamma (IFN-γ) and tumor necrosis factor alpha (TNF-α). Our group previously reported an increase of CD8+ T‐cell trafficking in the placenta with exposure to Lipopolysaccharides (LPS). CD8+ cytotoxic T cells have been classified into distinct subsets based upon cytokine production: Tc1 cells produce IFN-γ, Tc2 cells produce interleukin 4 (IL-4). Accordingly, the purpose of this research is to analyze the subsets of placenta CD8+ T cells. We hypothesized that LPS injection would induce a change of properties of CD8+ T cell and Tc1/Tc2 ratio. We investigated the subsets of CD8+ T cell infiltration to placenta and their specific function in response to LPS-induced inflammation in a mouse model. At embryonic (E) day 17, pregnant CD-1 dams received an intrauterine injection of 25 µg LPS in100 μl PBS or 100 μl of PBS only. Flow cytometry was used to quantify CD8+ T cells, evaluate the phenotype and subtypes, and detect markers of Tc1 and Tc2 cells in placenta, at 6 hours and 24 hours post injection (hpi). Intracellular staining and flow cytometry were performed to characterize cytokines produced by CD8+ T cells. Standard statistical analysis were employed. After 6 and 24 hours of LPS injection, total CD8 T cells increased (P<0.05). Tc1 cells expanded (P<0.05) in LPS-treated dams compared with the PBS group. The Tc1/Tc2 ratio was significantly higher in the LPS group than the PBS group (P<0.05). The expression of TNF-α and IFN-γ were increased in LPS group both at 6hpi and 24 hpi (P<0.05). We identified functional placental CD8+ T cell subtypes and found a significant increase ratio of Tc1/Tc2. Following IUI, CD8+ T cells induced inflammatory response in the placenta primarily via the production of Type 1 cytokines such as IFN-γ and TNF-α. We have provided evidence of a Tc1-bias response and cytokines in the mouse model of IUI.

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Section: Introductionmentioning

confidence: 99%

Type 1 Cytotoxic T Cells Increase in Placenta after Intrauterine Inflammation

Liu

Panda

et al. 2021

Front. Immunol.

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“…Thus the immunohistochemistry analysis confirms the anatomical location and fetal origin of the increased proportions of CD8+ T cells in villous tissue. The fetal (male) origin of the CD8+ T cells in placental villi is consistent with the absence of VUE, a lesion that is characterized by maternal immune infiltrates[20,28].…”

Section: Resultsmentioning

confidence: 83%

T cell Homeostatic Imbalance in Placentae from Women with HIV in the absence of Vertical Transmission

Ikumi

Pillay

Tilburgs

et al. 2021

Preprint

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BackgroundImplementation of Option B+ antiretroviral therapy (ART) has significantly lowered vertical transmission rates but has also increased numbers of HIV-exposed uninfected children (HEU), who remain vulnerable to morbidities. Here, we investigated whether altered immune status in HEU originates in the placenta.MethodsWe analyzed T cells from term placentae decidua and villous tissue and paired cord blood from pregnant women living with HIV (PWLWH) who initiated ART late in pregnancy (n=21) with HIV negative controls (n=9).ResultsPlacentae from PWLWH showed inverted CD4:CD8 ratios and higher proportions of tissue resident CD8+ T cells in villous tissue relative to control placentae. CD8+ T cells in the fetal capillaries, which were of fetal origin, positively correlated with maternal plasma viraemia prior to ART initiation, implying that imbalanced T cells persisted throughout pregnancy. Additionally, the expanded memory differentiation of CD8+ T cells was confined to the fetal placental compartment and cord blood, but was not observed in the maternal decidua.ConclusionT cell homeostatic imbalance in the blood circulation of PWLWH is reflected in the placenta. The placenta may be a causal link between HIV-induced maternal immune changes during gestation and altered immunity in newborn infants in the absence of vertical transmission.Lay SummaryThe effective prevention of HIV transmission during pregnancy with the rollout of antiretroviral therapy (ART) has resulted in increased numbers of HIV-exposed uninfected children (HEU). These children are vulnerable to infections and health problems and they have altered cellular immune systems at birth. We investigated whether these immune alterations may originate in the placenta, as this fetal organ maintains life during pregnancy. Do immune alterations in the newborn child originate in the placenta? After collecting placentae at term from pregnant women living with HIV (PWLWH), who started ART in the third trimester (n=21) and from HIV negative controls (n=9), we isolated T cells from dissected placental tissue and matching cord blood. Placentae from PWLWH showed inverted CD4:CD8 ratios in the placenta and cord blood with higher numbers of CD8+ T cells in the fetal part of the placenta. These CD8+ T cells mirrored events in the blood circulation of the mother and the altered balance of T cell immunity in the PWLWH was reflected in the placenta. Accordingly, the placenta may be a pivotal link between HIV-induced maternal immune changes and altered immunity in newborn infants in the absence of vertical transmission.

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“…Previous studies have suggested that PV fetal immune cells are limited to Hofbauer cells (Thomas et al, 2021) However, the increased granularity provided by single cell methods, have allowed for the detection of T cells, B cells and NK cells of fetal origin in healthy term placentas (Pique-Regi et al, 2019). Moreover, a recent study identified infiltrating cells in the PV to be largely of fetal origin in cases of infectious villitis (Enninga et al, 2020) and Erbach et al…”

Section: Discussionmentioning

confidence: 99%

“…In situ hybridization for the Y chromosome was adapted from the protocol outlined in (Enninga et al, 2020). Briefly, slides were deparaffinized with a series of xylene and ethanol washes.…”

Section: Fishmentioning

confidence: 99%

Human placental villi immune cells help maintain homeostasisin utero

Konnikova

Olaloye

et al. 2021

Preprint

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Maintenance of healthy pregnancy is reliant on successful balance between the fetal and maternal immune systems. Although maternal mechanisms responsible have been well studied, those used by the fetal immune system remain poorly understood. Using suspension mass cytometry and various imaging modalities, we report a complex immune system within the mid-gestation (17-23 weeks) human placental villi (PV). Further, we identified immunosuppressive signatures in innate immune cells and antigen presenting cells that potentially maintain immune homeostasis in utero. Consistent with recent reports in other fetal organs, T cells with memory phenotypes were detected within the PV tissue and vasculature. Moreover, we determined PV T cells could be activated to upregulate CD69 and proliferate after T cell receptor (TCR) stimulation and when exposed to maternal uterine antigens. Finally, we report that cytokine production by PV T cells is sensitive to TCR stimulation and varies between mid-gestation, preterm (26-35 weeks) and term deliveries (37-40 weeks). Collectively, we elucidated the complexity and functional maturity of fetal immune cells within the PV and highlighted their immunosuppressive potential.

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Maternal T Cells in the Human Placental Villi Support an Allograft Response during Noninfectious Villitis

Cited by 24 publications

References 58 publications

Type 1 Cytotoxic T Cells Increase in Placenta after Intrauterine Inflammation

Type 1 Cytotoxic T Cells Increase in Placenta after Intrauterine Inflammation

T cell Homeostatic Imbalance in Placentae from Women with HIV in the absence of Vertical Transmission

Human placental villi immune cells help maintain homeostasisin utero

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