Human regulatory T cells at the maternal-fetal interface show functional site-specific adaptation with tumor-infiltrating-like features

Wienke, Judith; Brouwers, Laura; Burg, Leone van der; Mokrý, Michal; Scholman, Rianne C.; Nikkels, Peter G. J.; Rijn, Bas B. van; Wijk, Femke van

doi:10.1101/820753

Cited by 7 publications

(6 citation statements)

References 140 publications

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“…Another unexpected finding is the upregulation of VDR in both JIA and RA SF Treg, on both transcriptional and epigenetic level, as well as in tumor-infiltrating Treg. Although not highlighted, high VDR levels were present in breast tumor-infiltrating Treg 14 and uterine eTreg 54 . Besides the well-known tolerogenic effects of vitamin D 3 55 , VDR is not well-studied in the Treg context, especially in humans.…”

Section: Discussionmentioning

confidence: 87%

Conserved human effector Treg signature is reflected in transcriptomic and epigenetic landscape

Mijnheer

Lutter

Mokrý

et al. 2020

Preprint

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Treg are critical regulators of immune homeostasis, and increasing evidence demonstrates that environment-driven Treg differentiation into effector (e)Treg is crucial for optimal functioning. However, human Treg programming under inflammatory conditions remains poorly understood. Here, we combine transcriptional and epigenetic profiling to identify the human eTreg core signature. Functional autoimmune inflammation-derived Treg display a unique transcriptional profile characterized by upregulation of both a core Treg (FOXP3, CTLA-4, TIGIT) and effector program (GITR, BLIMP-1, BATF). We identified a specific human eTreg signature that includes the vitamin D receptor (VDR) as predicted key-regulator in eTreg differentiation. H3K27ac/H3K4me1 occupancy revealed pronounced changes in the (super-)enhancer landscape, including enrichment of the binding motif for VDR and BATF. The observed Treg profile showed striking overlap with tumor-infiltrating Treg. Our data demonstrate that human inflammation-derived Treg acquire a specific eTreg profile guided by epigenetic changes. The core eTreg profile is conserved, and fine-tuned by environment-specific adaptations.

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Section: Discussionmentioning

confidence: 87%

Conserved human effector Treg signature is reflected in transcriptomic and epigenetic landscape

Mijnheer

Lutter

Mokrý

et al. 2020

Preprint

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“…PD‐1 hi cells did so in an IL‐10 dependent manner. At term, uterine Tregs express higher levels of FoxP3, CTLA‐4, and TIGIT compared with blood Tregs, and they have a signature of late‐stage effector differentiation and activation, characteristics that they share with tumor‐derived Tregs 110 . This FoxP3 + CTLA‐4 + TIGIT + phenotype suggests the presence of iTregs, which is in parallel with the notion that nTregs may be particularly important in early pregnancy, whereas iTregs become more relevant in late pregnancy 113 …”

Section: Maternal T Cells and Myeloid Cells In The Placental Bedmentioning

confidence: 83%

“…Pregnant women display an increased frequency of decidual CD4 + CD25 high FoxP3 + Tregs at term. 110 The majority of the Treg population in early pregnancy consists of nTregs (CD4 + Helios + ), and a decrease of nTregs in women with recurrent miscarriage suggests that these cells play a role in maintaining healthy pregnancy. 111 By using mass cytometry on isolated immune cells from decidual samples, we identified five different CD4 + CD25 + CD127 − Treg populations with differential expression of PD-1, TIGIT, CD39, and CCR4 over the course of pregnancy.…”

Section: Different Treg Populations In the Human Deciduamentioning

confidence: 99%

“…Pregnant women display an increased frequency of decidual CD4 + CD25 high FoxP3 + Tregs at term 110 . The majority of the Treg population in early pregnancy consists of nTregs (CD4 + Helios + ), and a decrease of nTregs in women with recurrent miscarriage suggests that these cells play a role in maintaining healthy pregnancy 111 .…”

Section: Maternal T Cells and Myeloid Cells In The Placental Bedmentioning

confidence: 99%

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Got your mother in a whirl: The role of maternal T cells and myeloid cells in pregnancy

Eikmans

Zwan

Claas

et al. 2020

HLA

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Appropriate development of the placenta is required for healthy pregnancy to occur. After implantation of the fertilized blastocyst, fetal trophoblasts invade the endometrium and myometrium of the mother's uterus to establish placentation. In this process, fetal trophoblasts encounter maternal immune cells. In this review, we focus on the role of maternal T cells and myeloid cells (macrophages, dendritic cells) in pregnancy and their interaction with trophoblasts. To retain immunologic tolerization, trophoblasts evade immune recognition by T cells and produce factors that modulate their phenotype and function. On top of that, the local environment at the maternal‐fetal interface favors expansion of regulatory T cells. Macrophages and dendritic cells are essential in maintaining a healthy pregnancy. They produce soluble factors and act as antigen‐presenting cells, thereby interacting with T cells. Herein, M2 macrophages, immature dendritic cells, CD4+ Th2 cells, and regulatory T cells represent an axis that maintains a local immune tolerant environment. We consider outstanding issues concerning these cell types and their pathways, which need to be addressed in future investigations. Data from recent single‐cell sequencing experiments of the placental bed, to study heterogeneity of maternal immune cells and to predict cell‐cell interactions, are discussed. Novel ways for long‐term culturing of primary trophoblasts allow for cell‐cell interaction studies in a functional way. Future directions should include study of the functionality of currently known and newly identified decidual immune cell subsets in healthy and complicated pregnancies, and their interaction with and modulation by trophoblast cells.

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“…Treg) [48,112], and POLR1A (cold-exposed Brown adipose tissue Treg) [113], suggesting the identified common variants could lead to functional defects in these specific Treg subsets. A third group of genes have been shown to regulate growth factor signaling pathways that are known to influence Treg differentiation and function [114][115][116].…”

Section: Filtered Treg Variants Identified In Other Autoimmune Diseasesmentioning

confidence: 99%

3DFAACTS-SNP: Using Regulatory T Cell-specific Epigenomics Data to Uncover Candidate Mechanisms of Type-1 Diabetes (T1D) risk

Liu

Sadlon

Wong

et al. 2021

Preprint

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BackgroundGenome-wide association studies (GWAS) have enabled the discovery of single nucleotide polymorphisms (SNPs) that are significantly associated with many autoimmune diseases including type 1 diabetes (T1D). However, many of the identified variants lie in non-coding regions, limiting the identification of mechanisms that contribute to autoimmune disease progression. To address this problem, we developed a variant filtering workflow called 3DFAACTS-SNP to link genetic variants to target genes in a cell specific manner. Here we use 3DFAACTS-SNP to identify candidate SNPs and target genes associated with the loss of immune tolerance in regulatory T cells (Treg) in T1D. ResultsUsing 3DFAACTS-SNP we identified from a list of 1,228 previously fine-mapped variants, 36 SNPs with plausible Treg-specific mechanisms of action. The integration of cell-type specific chromosome conformation capture data in 3DFAACTS-SNP, identified 119 regulatory regions and 51 candidate target genes that interact with these variant-containing regions in Treg cells. We further demonstrated the utility of the workflow by applying it to three other SNP autoimmune datasets, identifying 17 Treg-centric candidate variants and 35 interacting genes. Finally, we demonstrate the broad utility of 3DFAACTS-SNP for functional annotation of all known common (>10% allele frequency) variants from the Genome Aggregation Database (gnomAD). We identified 7,900 candidate variants and 3,245 candidate target genes, generating a list of potential sites for future T1D or autoimmune research. ConclusionsWe demonstrate that it is possible to further prioritise variants that contribute to T1D based on regulatory function and illustrate the power of using cell type specific multi-omics datasets to determine disease mechanisms. Our workflow can be customised to any cell type for which the individual datasets for functional annotation have been generated, giving broad applicability and utility.

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Human regulatory T cells at the maternal-fetal interface show functional site-specific adaptation with tumor-infiltrating-like features

Cited by 7 publications

References 140 publications

Conserved human effector Treg signature is reflected in transcriptomic and epigenetic landscape

Conserved human effector Treg signature is reflected in transcriptomic and epigenetic landscape

Got your mother in a whirl: The role of maternal T cells and myeloid cells in pregnancy

3DFAACTS-SNP: Using Regulatory T Cell-specific Epigenomics Data to Uncover Candidate Mechanisms of Type-1 Diabetes (T1D) risk

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