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The transcription factor PBX1 drives natural killer cells to promote fetal development

ABSTRACT: Perfect fetal development is a solid foundation for successful fertility, in which the abundant natural killer (NK) cells in the decidua tissue at the maternal-fetal interface play an important role during the first trimester. The functional subsets and transcriptional regulation mechanisms of decidual NK (dNK) cells remain poorly understood. Here, we identified CD49a+PBX1+ dNK cells as a unique subset of NK cells that promote fetal development in both human and mice. PBX1 drove the transcription of key functional molecules pleiotrophin and osteoglycin that promote fetal development through direct promoter binding. In patients with unexplained recurrent spontaneous abortion (URSA), decreased expression of PBX1 and PBX1(G21S) mutation correlated with fetal growth restriction and pregnancy failure. Inactivation of Pbx1 in mouse NK cells caused impaired fetal development due to a decrease in growth promoting factors. Our observations reveal the molecular regulation mechanism of CD49a+PBX1+ dNK cells promoting fetal development, and indicate that impaired PBX1 in dNK cells may serve as pathogenesis and biomarker of URSA.

ORGANISM(S): Homo sapiens

PROVIDER: GSE110244 | GEO | 2021/01/01

REPOSITORIES: GEO

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Natural killer cells promote fetal development through the secretion of growth-promoting factors

Project description:Natural killer (NK) cells are present in large populations at the maternal-fetal interface during early pregnancy, but their roles in fetal growth are unclear. Here, we identify a CD49a+Eomes+ subset of NK cells that have the capability to secrete growth-promoting-factors (GPF), including pleiotrophin, osteoglycin and osteopontin in both humans and mice. Decreases in this GPF-secreting NK subset impair fetal development, and leads to fetal growth restriction. The transcriptional factor Nfil3 but not T-bet affects the function and the number of this decidual NK subset. The crosstalk of the HLA-G-ILT2-KIR2DL4 axis promotes the GPF-secreting function of this NK subset. Adoptive transfer of these induced CD49a+Eomes+NK cells can reverse the impaired fetal growth and rebuild an appropriate local microenvironment. These findings reveal new properties of NK cells in promoting fetal growth as well as novel approaches for therapeutically administering NK cells to reverse restricted nourishments within the microenvironment during early pregnancy. To investigate novel molecular signatures of human decidual NK cells, we performed microarray analysis on dNK cells (CD3−CD56+CD49a+CD49b−) and pNK cells (CD3−CD56+CD49a−CD49b+). dNK cells were purified from first-trimester deciduas. pNK cells were purified from adult peripheral blood mononuclear cells. Samples were collected from healthy adult donors after obtaining informed consent according to the Ethics Committee of the University of Science & Technology of China.

2018-01-04 | GSE97217 | GEO

Human-induced CD49a+ NK cells promote fetal growth

Project description:CD49a+ natural killer (NK) cells are critical in promoting fetal development and maintaining immune tolerance at the maternal-fetal interface in early pregnancy. However, their tissue residency in human tissue hinder thorough studies and clinical application. How to induce functional human CD49a+ NK cells that could benefit pregnancy outcomes is still unknown. Here, we have established three no feeder cell induction systems to induce human CD49a+ NK cells from umbilical cord blood hematopoietic stem cells (HSCs), bone marrow HSCs or peripheral blood NK cells, respectively. These induced NK cells (iNKs) from three cell induction systems show high expression of CD49a, CD9, CD39, CD151, low expression of CD16, and no obvious cytotoxic capability, phenotypically and functionally similar with decidual NK cells. Furthermore, these iNKs also have high expression of growth-promoting factors and proangiogenic factors. Importantly, these iNKs have shown their capabilities to promote fetal growth and improve uterine artery blood flow in a murine pregnancy model in vivo. This research reveals properties of human-induced CD49a+ NK cells in promoting fetal growth from three cell induction systems, which may improve the feasibility of applying these iNKs to the patients having adverse pregnancy outcomes.

2022-02-23 | GSE184719 | GEO

Human-induced CD49a+ NK cells promote fetal growth

Project description:Human-induced CD49a+ NK cells promote fetal growth

| PRJNA765937 | ENA

a26bf570-482e-435d-a268-fddc7e54b31d - samples

Project description:The dataset contains RNAseq data from 5 subsets of NK cells isolated from human lung: 1) CD69+CD49a+CD103+CD16-CD56bright NK cells 2) CD69+CD49a+CD103-CD16-CD56bright NK cells 3) CD69+CD49a-CD103-CD16-CD56bright NK cells 4) CD69-CD49a-CD103-CD16-CD56bright NK cells 5) CD56dimCD16+NKG2A+CD57- NK cells The dataset contains paired data for the subsets from 2 donors with 2 biological replicates/donor and subset.

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CD49a+ and CD49a- NK cells from human livers

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Expression data of human decidual NK cells from gravid uteri and NK cells from cycling endometrium

Project description:Human NK cells from the decidua basalis of gravid uteri (dNK) and from cycling endometrium (eNK) of women undergoing hysterectomy were isolated and compared by gene expression profiling using Affymetrix microarrays with probes representing ~47,400 transcripts. Substantial differences indicate that these two types of NK cells represent distinct subsets. Freshly isolated NK cells were obtained by FACS sorting. 4 dNK and 5 eNK samples were obtained form independent donors. dNK cells were isolated from the decidua basalis of first trimester placentas and sorted as CD3-, CD16-, CD56+ cells. eNK cells were obtained from non-affected regions of cycling endometrium of donor women undergoing hysterectomy and were sorted as CD45+, CD56+, CD3- cells . The preliminary patient diagnoses included genital prolapse, fibroids, cervical dysplasia, or menorrhagia. All cycling endometrium samples were from the secretory phase of the cycle with exception of sample eNK_S6 that was from the proliferative phase.

2010-03-09 | E-GEOD-20499 | biostudies-arrayexpress

microRNA expression in innate lymphoid cells from human decidua

Project description:Innate lymphoid cells are a heterogeneous subset of lymphocytes deeply implicated in the innate immune responses to different pathogens, in lymphoid organogenesis and in the maintenance of tissue homeostasis. Group 3 innate lymphoid cells (ILC3) have been detected in human decidua, where they play a role in the early inflammatory phase favoring implantation and tissue remodeling as well as in the subsequent regulatory phase preventing fetal rejection and supporting neoangiogenesis. A balance between inflammation and immune tolerance is required to maintain pregnancy, thus maternal immune system must be controlled by finely tuned mechanisms. MicroRNAs (miRNAs) are small non-coding RNAs with important regulatory roles in immune cells, but their function in decidual ILC3 (dILC3) and decidual NK (dNK) cells is still undefined. Here, we examined the miRNome by microarray in these cells during the first trimester of pregnancy and compared with miRNA profiles of peripheral blood NK (pbNK) cells from pregnant women. We show that distinct miRNA profiles could clearly distinguish dILC3 from NK cells. Correlation analyses revealed that dNK and pbNK miRNome profiles are more similar to each other as compared to dILC3. Overall, our data identified specific miRNA signatures distinguishing dILC3, dNK and pbNK cells.

2020-02-28 | GSE140606 | GEO

RNA sequencing of NK cells in human lung

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Project description:Characterisation of NKG2C+KIR+ tissue-resident NK cells in human lung and CD49a+ CD56bright NK cells in human blood.

2021-03-24 | GSE166654 | GEO

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Project description:Adaptive features of natural killer (NK) cells have been reported in various species with different underlying mechanisms. It is unclear, however, which NK cell populations are capable of mounting antigen-specific recall responses, and how such functions are regulated at the molecular level. Here we identify and characterize a discrete population of CD49a+CD16- NK cells in the human liver that display increased epigenetic potential to elicit memory responses and has the functional properties to exert antigen-specific immunity on the skin as an effector site. Integrated chromatin-based epigenetic and transcriptomic profiling revealed unique characteristics of hepatic CD49a+CD16- NK cells when compared to conventional CD49a-CD16+ NK cells thereby defining active genomic regions and molecules underpinning distinct NK cell reactivity. In contrast to conventional NK cells, our results suggest adaptive CD49a+CD16- NK cells to be able to bypass the KIR receptor-ligand system upon antigen-specific stimulation. Furthermore, these cells were highly migratory towards chemokine gradients expressed in epicutaneous patch test lesions as an effector site of adaptive immune responses of the skin. These results define pathways operative in human antigen-specific memory NK cells and provide a roadmap for harnessing this NK cell subset for specific therapeutic or prophylactic vaccine strategies.

2020-10-15 | GSE158485 | GEO

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