TGFb1 suppresses the activation of distinct dNK subpopulations in preeclampsia

Zhang, Jianhong; Dunk, Caroline; Shynlova, Oksana; Caniggia, Isabella; Lye, Stephen J.

doi:10.1016/j.ebiom.2018.12.015

Cited by 61 publications

(47 citation statements)

References 47 publications

(49 reference statements)

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“…Importantly, the use of FISH-flow cytometry for this purpose was necessitated by the failure of multiple antibodies to detect VEGF-A using standard intracellular staining protocols. This result, which contrasts with other publications that used the same anti-VEGF-A antibodies for this purpose (10,(21)(22)(23)(24), highlights the need for robust positive and negative controls in such assays. Moving forward, future studies may make use of FISH-flow cytometry to evaluate VEGFA expression among tissue-resident or tumor-infiltrating NK and ILC1 cells, with the goal of determining if there is an ex vivo association between VEGFA expression and the TGF-βassociated ILC1-like phenotype.…”

Section: Discussioncontrasting

confidence: 80%

The Production of Pro-angiogenic VEGF-A Isoforms by Hypoxic Human NK Cells Is Independent of Their TGF-β-Mediated Conversion to an ILC1-Like Phenotype

2020

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Circulating natural killer (NK) cells have been shown to adopt a type 1 innate lymphoid cell (ILC1)-like phenotype in response to TGF-β and secrete VEGF-A when exposed to hypoxia. Although these changes are often considered to be linked attributes of tissue residency, it has yet to be determined if TGF-β and hypoxia work in concert to coordinate NK cellular phenotype and angiogenic potential. Examination of human circulating NK cells treated with TGF-β demonstrated heterogeneity in their potential to adopt an ILC1-like phenotype, as indicated by the upregulation of CD9 and CD103 on only a subset of cells in culture. Culturing NK cells in chronic hypoxia did not induce a similar ILC1-like conversion and did not enhance the degree of conversion for cells exposed to TGF-β. Similarly, hypoxic culture of circulating NK cells induced VEGF-A secretion, but this production was not enhanced by TGF-β. Fluorescent in-situ hybridization flow cytometry demonstrated that hypoxia-induced VEGF-A production was uniform across all NK cells in culture and was not a selective feature of the cellular subset that adopted an ILC1-like phenotype in response to TGF-β. Examination of VEGF-A isoforms demonstrated that hypoxia induces the production of pro-angiogenic VEGF-A isoforms, including VEGF-A 165 and VEGF-A 121 , and does not stimulate any meaningful production of anti-angiogenic isoforms, such as VEGF-A b transcriptional variants or VEGF-Ax. In summary, TGF-β-mediated ILC1-like conversion and hypoxia-induced VEGF-A production are discrete processes in NK cells and are not part of a linked cellular program associated with tissue residency.

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Section: Discussioncontrasting

confidence: 80%

The Production of Pro-angiogenic VEGF-A Isoforms by Hypoxic Human NK Cells Is Independent of Their TGF-β-Mediated Conversion to an ILC1-Like Phenotype

2020

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“…Apart from fetal immune tolerance, Tregs also suppress activity of other decidual immune cells. Indeed, Treg secretion of TGFβ and IL10 downregulate decidual NK cell activation, and this suppression is protective against pregnancy complications such as pre-eclampsia and recurrent abortions (211,212). However, the numbers of CD3 + CD8 − FOXP3 + Tregs at the maternalfetal interface did not change upon intraamniotic LPS exposure in Rhesus macaques (84).…”

Section: Maternal-fetal Tolerance and Tregsmentioning

confidence: 99%

Immunobiology of Acute Chorioamnionitis

2020

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Acute chorioamnionitis is characterized by neutrophilic infiltration and inflammation at the maternal fetal interface. It is a relatively common complication of pregnancy and can have devastating consequences including preterm labor, maternal infections, fetal infection/inflammation, fetal lung, brain, and gastrointestinal tract injury. In this review, we will discuss current understanding of the pathogenesis, immunobiology, and mechanisms of this condition. Most commonly, acute chorioamnionitis is a result of ascending infection with relatively low-virulence organisms such as the Ureaplasma species. Furthermore, recent vaginal microbiome studies suggest that there is a link between vaginal dysbiosis, vaginal inflammation, and ascending infection. Although less common, microorganisms invading the maternal-fetal interface via hematogenous route (e.g., Zika virus, Cytomegalovirus, and Listeria) can cause placental villitis and severe fetal inflammation and injury. We will provide an overview of the knowledge gleaned from different animal models of acute chorioamnionitis and the role of different immune cells in different maternal-fetal compartments. Lastly, we will discuss how infectious agents can break the maternal tolerance of fetal allograft during pregnancy and highlight the novel future therapeutic approaches.

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“…TGF-β is produced by and has an immunomodulatory effect on multiple cell types present in the decidua (111)(112)(113)(114)(115)(116)(117)(118)(119)(120). In the early implantation phase, TGF-β is important for trophoblast invasion in the endometrium (121,122).…”

Section: Tgf-βmentioning

confidence: 99%

“…TGF-β can inhibit NK cell and T cell activation and proliferation by repressing the mammalian target of rapamycin (mTOR) signaling pathway (126,127), and similarly, suppress activation of dNK cells (120). Since dNK cells are important contributors to angiogenesis at the maternal-fetal interface, their cytotoxicity needs to be suppressed but they should still be able to execute their role in angiogenesis.…”

Section: Tgf-βmentioning

confidence: 99%

“…Since dNK cells are important contributors to angiogenesis at the maternal-fetal interface, their cytotoxicity needs to be suppressed but they should still be able to execute their role in angiogenesis. A balanced TGF-β level may, therefore, be important to maintain correct functioning of dNK cells (120). Furthermore, TGF-β can affect T cells directly by inhibiting their proliferation and differentiation (128,129), and indirectly by its inhibitory effect on APCs.…”

Section: Tgf-βmentioning

confidence: 99%

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Regulatory T Cells in Pregnancy: It Is Not All About FoxP3

et al. 2020

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In pregnancy, the semi-allogeneic fetus needs to be tolerated by the mother's immune system. Regulatory T cells (Tregs) play a prominent role in this process. Novel technologies allow for in-depth phenotyping of previously unidentified immune cell subsets, which has resulted in the appreciation of a vast heterogeneity of Treg subsets. Similar to other immunological events, there appears to be great diversity within the Treg population during pregnancy, both at the maternal-fetal interface as in the peripheral blood. Different Treg subsets have distinct phenotypes and various ways of functioning. Furthermore, the frequency of individual Treg subsets varies throughout gestation and is altered in aberrant pregnancies. This suggests that distinct Treg subsets play a role at different time points of gestation and that their role in maintaining healthy pregnancy is crucial, as reflected for instance by their reduced frequency in women with recurrent pregnancy loss. Since pregnancy is essential for the existence of mankind, multiple immune regulatory mechanisms and cell types are likely at play to assure successful pregnancy. Therefore, it is important to understand the complete microenvironment of the decidua, preferably in the context of the whole immune cell repertoire of the pregnant woman. So far, most studies have focused on a single mechanism or cell type, which often is the FoxP3 positive regulatory T cell when studying immune regulation. In this review, we instead focus on the contribution of FoxP3 negative Treg subsets to the decidual microenvironment and their possible role in pregnancy complications. Their phenotype, function, and effect in pregnancy are discussed.

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TGFb1 suppresses the activation of distinct dNK subpopulations in preeclampsia

Cited by 61 publications

References 47 publications

The Production of Pro-angiogenic VEGF-A Isoforms by Hypoxic Human NK Cells Is Independent of Their TGF-β-Mediated Conversion to an ILC1-Like Phenotype

The Production of Pro-angiogenic VEGF-A Isoforms by Hypoxic Human NK Cells Is Independent of Their TGF-β-Mediated Conversion to an ILC1-Like Phenotype

Immunobiology of Acute Chorioamnionitis

Regulatory T Cells in Pregnancy: It Is Not All About FoxP3

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