Dominant IL‐10 and TGF‐β mRNA Expression in γδT Cells of Human Early Pregnancy Decidua Suggests Immunoregulatory Potential

Nagaeva, Olga; Jönsson, Lena; Mincheva‐Nilsson, Lucia

doi:10.1034/j.1600-0897.2002.01131.x

Cited by 152 publications

(136 citation statements)

References 40 publications

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“…These data are in agreement with those from other research groups (10, 17). Moreover, IL-10 levels were significantly diminished and TGF-␤ levels were slightly diminished in pathological pregnancies compared with normal pregnancies, further suggesting low Treg numbers in pathological pregnancies, since Treg are known to affect immune responses by secreting antiinflammatory cytokines at the fetal-maternal interface (14,61,67). Thus, our data on low levels of hCG coinciding with low levels of Treg-associated molecules suggest that hCG may be chiefly responsible for Treg attraction to the fetal-maternal interface.…”

Section: Discussionmentioning

confidence: 66%

“…The suppressive function of Treg is mediated either via cell-cell contact (11) or by secretion of immunosuppressive cytokines such as IL-10 and TGF-␤ (12)(13)(14)(15)(16). Additionally, it has been demonstrated that the proportion of decidual Treg was significantly lower in specimens from spontaneous abortion compared with those from induced abortions (10).…”

Section: Cd25mentioning

confidence: 99%

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Human Chorionic Gonadotropin Attracts Regulatory T Cells into the Fetal-Maternal Interface during Early Human Pregnancy

Schumacher

Brachwitz

Sohr

et al. 2009

The Journal of Immunology

278

218

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Regulatory T cells (Treg) expand during pregnancy and are present at the fetal-maternal interface at very early stages in pregnancy. The migration mechanisms of Treg to the pregnant uterus are still unclear. Human chorionic gonadotropin (hCG) is secreted by the blastocyst immediately after fertilization and has chemoattractant properties. Therefore, we sought to analyze whether hCG secreted by early trophoblasts attracts Treg to the uterus and hence contributes to maternal tolerance toward the fetus. Decidua and placenta tissue samples from patients having spontaneous abortions or ectopic pregnancies were employed to evaluate Treg and hCG levels. Age-matched samples from normal pregnant women served as controls. We further performed in vitro studies with primary first trimester trophoblast cells and a choriocarcinoma cell line (JEG-3) aiming to evaluate the ability of secreted hCG to attract Treg. Patients having miscarriages or ectopic pregnancy presented significantly decreased hCG mRNA and protein levels associated with decreased Foxp3, neuropilin-1, IL-10, and TGF-β mRNA levels as compared with normal pregnant women. Using migration assays we demonstrated that Treg were attracted by hCG-producing trophoblasts or choriocarcinoma cells. Treg migration toward cells transfected with hCG expression vectors confirmed the chemoattractant ability of hCG. Our data clearly show that hCG produced by trophoblasts attracts Treg to the fetal-maternal interface. High hCG levels at very early pregnancy stages ensure Treg to migrate to the site of contact between paternal Ags and maternal immune cells and to orchestrate immune tolerance toward the fetus.

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Section: Discussionmentioning

confidence: 66%

Section: Cd25mentioning

confidence: 99%

Human Chorionic Gonadotropin Attracts Regulatory T Cells into the Fetal-Maternal Interface during Early Human Pregnancy

Schumacher

Brachwitz

Sohr

et al. 2009

The Journal of Immunology

278

218

View full text Add to dashboard Cite

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“…Human Vd1 T cells have been observed to be recruited to the maternal/fetal interface during pregnancy where their activation is believed to play a role in the induction of tolerance to paternal antigens. 15,[51][52][53][54] Furthermore, there is evidence suggesting that the early pregnancy human decidua is actually a site of extrathymic maturation of Vd1 T cells. 55,56 This enrichment of cd T cells at the maternal/fetal interface and their mysterious role in pregnancy is not unique to humans as the same has been observed in sheep 57 and mice 58 , suggesting a central conserved role of cd T cells involved in pregnancy-related immune changes.…”

Section: Missingmentioning

confidence: 99%

Defining the nature of human γδ T cells: a biographical sketch of the highly empathetic

2012

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The elusive task of defining the character of cd T cells has been an evolving process for immunologists since stumbling upon their existence during the molecular characterization of the a and b T cell receptor genes of their better understood brethren. Defying the categorical rules used to distinctly characterize lymphocytes as either innate or adaptive in nature, cd T cells inhabit a hybrid world of their own. At opposing ends of the simplified spectrum of modes of antigen recognition used by lymphocytes, natural killer and ab T cells are particularly well equipped to respond to the 'missing self' and the 'dangerous non-self', respectively. However, between these two reductive extremes, we are chronically faced with the challenge of making peace with the 'safe non-self' and dealing with the inevitable 'distressed self', and it is within this more complex realm cd T cells excel thanks to their highly empathetic nature. This review gives an overview of the latest insights revealing the unfolding story of human cd T cells, providing a biographical sketch of these unique lymphocytes in an attempt to capture the essence of their fundamental nature and events that influence their life trajectory. What hangs in their balance is their nuanced ability to differentiate the friends from the foe and the pathological from the benign to help us adapt swiftly and efficiently to life's many stresses. Keywords: antigen recognition; danger-associated molecular patterns; gamma delta T cell subsets; immune homeostasis; innate immunity; stress response PROLOGUE Since the time of their accidental discovery during the molecular characterization of the a and b T cell receptor (TCR) genes belonging to their relatively unambiguous brethren, 1 'enigmatic' is still one of the most commonly used adjectives to describe cd T cells. This can be attributed to the fact that these unconventional lymphocytes have thus far been remarkably successful in thwarting most attempts at definition. Much of what we know about T cell biology and function comes from what has been discerned through studies done on ab T cells; however, one thing that is certain is that the majority of the rules governing the lives of ab T cells are surprisingly irrelevant when it comes to understanding the elusive character of cd T cells. Table 1 highlights some of the major differences between these two T cell subsets in humans.Recognition by cd T cells is not typically in the context of classical major histocompatibility complex (MHC) class I or II molecules and neither is antigen processing required. 2,3 These observations are corroborated by the fact that the majority of cd T cells are CD8 and CD4 negative. Crystal structure analysis of the cd TCR determined that the length and conformation of cd TCR resemble immunoglobulins (Ig) more than the ab TCR, which was taken to suggest that antigen recognition by cd T cells may be more similar to the binding of antibody to antigen rather than the MHC/peptide complex recognized by ab T cells. 4 The very basis of foreign antigen rec...

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“…After incubation, total RNA was isolated and cDNA transcribed as previously described (27). Real-time quantitative RT-PCR was performed with specific primers and probes for perforin as described below.…”

Section: Analysis Of the Effect Of Nkg2d Ligand-expressing Placental mentioning

confidence: 99%

“…Total RNA and cDNA were obtained from laser microdissected and isolated STB and from purified lymphocyte subpopulations incubated in the presence or absence of exosomes. ULBPs were amplified from STB cDNA and perforin from NK, CD8 ϩ , and ␥␦ T cell cDNA on ABI PRISM 7700 by TaqMan Gene Expression Plate (I) protocol (PE Applied Biosystems) as described (27). Primer and probe sequences, detecting all five ULBP members, were as follows: ULBP1/RAET1I (forward) 5Ј-GATCCAACAAAACCACCCTC TCT, (reverse) 5Ј-ACTTTCCACCTGTCACTCTAAACAAC, (probe) 5Ј-TGGCCACCACCCTCAGTCCCTG; ULBP2/RAET1H (forward) 5Ј-AG GAGCACCACTCGCCAT, (reverse) 5Ј-AGGAGCCTTTTGGTATCAGC TT, (probe) 5Ј-TGCTTCATCCTCCCTGGCATCTGA; ULBP3/RAET1N (forward) 5Ј-CACAGCACCACCCACCAT, (reverse) 5Ј-TCACCTTCCA CCTGTCACTCTAA, (probe) 5Ј-TGCTTCATCCTCCCTGGCATCTGA; ULBP4/RAT1E (forward) 5Ј-CTGCAAGTCGAGATGTTTTGTCA, (reverse) 5Ј-AAAGAGGAGGGATTTCTCTCCAT, (probe) 5Ј-TGCACTGG TGCATCCTGGCAGTT; and ULBP5/RAET1G (forward) 5Ј-CACAGT CTGACCCAAAGCCA, (reverse) 5Ј-GGTAGCTGTCACTCCAAAGGAC TC, (probe) 5Ј-TGGCCACCACCCTCAGTCCCTG.…”

Section: Dna and Total Rna Extraction And Quantitative Real-time Pcr mentioning

confidence: 99%

Human Placenta Expresses and Secretes NKG2D Ligands via Exosomes that Down-Modulate the Cognate Receptor Expression: Evidence for Immunosuppressive Function

Hedlund¹,

Stenqvist²,

Nagaeva³

et al. 2009

The Journal of Immunology

Self Cite

290

266

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During mammalian pregnancy maternal-fetal tolerance involves a number of immunosuppressive factors produced by placenta. Recently, placenta-derived exosomes have emerged as new immune regulators in the maternal immune tolerance. Exosomes are membrane nanovesicles with defined morphology, which are secreted from endosomal multivesicular bodies (MVB) upon fusion with the plasma membrane. Previously, we reported that the MHC class I chain-related (MIC) proteins A and B, human ligands of the activating NK cell receptor NKG2D, are expressed by placenta, sorted to MVB of syncytiotrophoblast and probably released via MIC-bearing exosomes. In this report, we show that the second family of human NKG2D ligands, the UL-16 binding proteins (ULBP), is also expressed by placenta. Importantly, this expression was not due to placental CMV infection. Immunoelectron microscopy disclosed that ULBP1–5 are produced and retained in MVB of the syncytiotrophoblast on microvesicles/exosomes. Using human placenta explant cultures and different assays, we demonstrate that exosomes bearing NKG2D ligands are released by human placenta. Isolated placental exosomes carried ULBP1–5 and MIC on their surface and induced down-regulation of the NKG2D receptor on NK, CD8+, and γδ T cells, leading to reduction of their in vitro cytotoxicity without affecting the perforin-mediated lytic pathway. Release of placental NKG2D ligands via exosomes is an alternative mechanism for generation of bioactive soluble form of these ligands. These findings highlight a role for NKG2D ligand-bearing placental exosomes in the fetal immune escape and support the view of placenta as a unique immunosuppressive organ.

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Dominant IL‐10 and TGF‐β mRNA Expression in γδT Cells of Human Early Pregnancy Decidua Suggests Immunoregulatory Potential

Cited by 152 publications

References 40 publications

Human Chorionic Gonadotropin Attracts Regulatory T Cells into the Fetal-Maternal Interface during Early Human Pregnancy

Human Chorionic Gonadotropin Attracts Regulatory T Cells into the Fetal-Maternal Interface during Early Human Pregnancy

Defining the nature of human γδ T cells: a biographical sketch of the highly empathetic

Human Placenta Expresses and Secretes NKG2D Ligands via Exosomes that Down-Modulate the Cognate Receptor Expression: Evidence for Immunosuppressive Function

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