MIC-1 (a multifunctional modulator of dendritic cell phenotype and function) is produced by decidual stromal cells and trophoblasts

Segerer, Sabine; Rieger, Lorenz; Kapp, Michaela; Dombrowski, Yvonne; Müller, Nora; Dietl, Johannes; Kämmerer, Ulrike

doi:10.1093/humrep/der358

Cited by 69 publications

(55 citation statements)

References 42 publications

(55 reference statements)

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“…They are poorly characterized with regard to their distinctive phenotype, anatomical localization, and function, however, appear to be important in embryo implantation and, most likely, in regulating placenta-specific tolerance to the semiallograft [28,40,41]. There are several reports documenting that DCs conditioned by trophoblasts in vitro fail to promote expansion of T cells or stimulate differentiation of regulatory T cells, which was mainly attributed to the production of soluble mediators such as IDO, TSLP,33,42,43]. Though we cannot exclude that soluble mediators may contribute in DC silencing by choriocarcinoma cells in our system, these are unlikely to contribute in cocultures involving CHO transfectants, which would only release hamster-specific factors not triggering a response in human target cells.…”

Section: Discussionmentioning

confidence: 99%

Human endogenous retrovirus envelope proteins target dendritic cells to suppress T‐cell activation

et al. 2015

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Though mostly defective, human endogenous retroviruses (HERV)can retain open reading frames, which are especially expressed in the placenta. There, the envelope (env) proteins of HERV-W (Syncytin-1), HERV-FRD (Syncytin-2), and HERV-K (HML-2) were implicated in tolerance against the semi-allogenic fetus. Here, we show that the known HERV envbinding receptors ASCT-1 and -2 and MFSD2 are expressed by DCs and T-cells. When used as effectors in coculture systems, CHO cells transfected to express Syncytin-1, -2, or HML-2 did not affect T-cell expansion or overall LPS-driven phenotypic DC maturation, however, promoted release of IL-12 and TNF-α rather than IL-10. In contrast, HERV env expressing choriocarcinoma cell lines suppressed T-cell proliferation and LPS-induced TNF-α and IL-12 release, however, promoted IL-10 accumulation, indicating that these effects might not rely on HERV env interactions. However, DCs conditioned by choriocarcinoma, but also transgenic CHO cells failed to promote allogenic T-cell expansion. This was associated with a loss of DC/T-cell conjugate frequencies, impaired Ca 2+ mobilization, and aberrant patterning of f-actin and tyrosine phosphorylated proteins in T-cells. Altogether, these findings suggest that HERV env proteins target T-cell activation indirectly by modulating the stimulatory activity of DCs.Keywords: DCs r DC/T-cell conjugates r HERV r Immune tolerance r Immunological synapse r T-cell activation Additional supporting information may be found in the online version of this article at the publisher's web-site IntroductionHuman endogenous retroviruses (HERVs) are estimated to comprise about 8% of the human genome [1]. They are mainly germline transmitted. HERVs are typically defective as a result of multiple mutations in their genomes, and it is therefore only on exception that viral particles can be produced [1,2]. Endogenous retroviruses (ERVs) can substantially regulate host cell gene expression and functions. In addition to viral transcripts, ERV encoded proteins translated from intact ORFs were implicated Correspondence: Dr. Sibylle Schneider-Schaulies e-mail: s-s-s@vim.uni-wuerzburg.de in both pathological and physiological processes [3]. The latter has for instance been revealed for the envelope (env) regions of three HERVs (ERV-3, HERV-W, and HERV-FRD). These are highly expressed in early and late placentae, and their importance in successful accomplishment of pregnancy has been suggested [4][5][6][7][8][9][10], not least because spontaneous abortions or complications of gestation like preeclampsia are associated with reduced levels of HERV env proteins [11,12]. In fact, their expression has been found crucial in the intrauterine fetal development in promoting syncytiotrophoblast formation, while the HERV-FRD env was also associated with fetomaternal tolerance to prevent rejection of the fetus [13][14][15][16][17].Immunodeficiency is commonly associated with retroviral infections (for a recent review see [18] effector mechanisms studied, immunosuppressive domains (ISD) we...

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Section: Discussionmentioning

confidence: 99%

Human endogenous retrovirus envelope proteins target dendritic cells to suppress T‐cell activation

et al. 2015

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“…19,20 DSCs and trophoblasts can produce macrophage inhibitory cytokine 1 which modulates the dendritic cell phenotype with a tolerogenic subtype in decidua. 21 As a key component of human placenta, trophoblasts are the only embryo-derived cells that interact directly with mother-derived cells. Human placental cytotrophoblasts produce the immunosuppressive cytokine IL-10 and the Th2-dominant cytokine IL-4 which promote trophoblast invasion and cause Th2 polarization and maternal-fetal tolerance.…”

Section: Introductionmentioning

confidence: 99%

The CXCL12/CXCR4 axis is involved in the maintenance of Th2 bias at the maternal/fetal interface in early human pregnancy

Piao

Zhu

et al. 2012

Cell Mol Immunol

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The regulatory mechanism of Th2 bias at the maternal/fetal interface remains unclear. In this study, we characterized cytokine production in decidual stromal cells (DSCs), decidual immune cells (DICs) and embryo-derived trophoblast cells, and investigated the regulation of CXCL12/CXCR4 interaction on Th2 bias at the maternal/fetal interface in early human pregnancy. We found differential production of Th1-type and Th2-type cytokines by trophoblasts, DSCs and DICs. The secretion of these cytokines varied in different cell cocultures, conduced to Th2 bias. Flow cytometry showed that coculture of trophoblasts with DSCs and DICs significantly increased IL-4 and IL-10 production in trophoblasts, and IL-10 production in DSCs. However, the coculture of trophoblasts with DSCs and DICs significantly increased interferon (IFN)-c expression in DSCs, and tumor-necrosis factor (TNF)-a expression in DICs. No change was seen in Th1-type cytokine production in trophoblasts, and in Th2-type cytokine production in DICs in all cocultures. Furthermore, pre-treatment with anti-CXCR4 neutralizing antibody upregulated the production of the Th1-type cytokines IFN-c and TNF-a, and downregulated the production of the Th2-type cytokines IL-4 and IL-10, in trophoblasts, DSCs, DICs or their cocultures. Interestingly, rhCXCL12 inhibited production of the Th1-type cytokine TNF-a and enhanced the expression of the Th2-type cytokines such as IL-4 and IL-10 in DICs; this effect was abrogated by anti-CXCR4 antibody. Our present study has elucidated the individual contributions of component cells to the shaping of Th2 bias, and uncovered a complicated cross-talk via the CXCL12/CXCR4 signal at the maternal/fetal interface in early human pregnancy.

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“…Макрофагингибирующий цитокин-1 (MIC-1), другой член семейства TGF-β, продуцируемый в больших количествах клетками трофобласта и деци-дуальной стромы, нарастает в циркуляции и оказы-вает плейотропный эффект на различные физиоло-гические процессы в ходе беременности [72]. Он ак-тивирует миграцию толерогенных (незрелых) DC, подавляет экспрессию костимуляторных молекул в процессе их созревания и способность активировать пролиферацию Т-лимфоцитов в ответ на аллоген-ную стимуляцию.…”

Section: другие факторыunclassified

Mechanisms of maternal tolerance to the fetus: lessons of molecular diplomacy

Ablamunits¹

2016

Probl. reprod.

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Механизмы толерантности матери к плоду: уроки молекулярной дипломатии К.м.н., доц. В.Г. АблАмуниц Санкт-Петербургский государственный педиатрический медицинский университет, Санкт-Петербург, Россия, 194100 настоящий обзор посвящен анализу современных данных о факторах, обеспечивающих иммунологическую неприкосновенность плода в организме матери. Взаимодействие сигналов с обеих сторон -гормонов, молекул мнС, цитокинов, индукторов апоптоза, ингибиторов комплемента -напоминает сложную сеть дипломатических отношений, направленных на урегулирование, казалось бы, неизбежного иммунного конфликта. this review analyses our current knowledge of the factors mediating maternal tolerance to the fetus. interaction of signals from both mother and fetus -hormones, mHC molecules, cytokines, inducers of apoptosis, complement inhibitors -resembles a complex diplomatic network aimed at settling a seemingly inevitable immune conflict. Keywords: HLA-G, allotransplant, apoptosis, maternal tolerance to the fetus.Огромное число живых существ на планете Зем-ля размножается половым путем, который обеспечи-вает им важное преимущество -возможность ком-бинировать генетический материал, а следовательно -привносить разнообразие, столь существенное для выживания и эволюции вида. Более сложные формы жизни -позвоночные -приобрели высоко-развитую систему специфического иммунитета, за-щищающую их от патогенов, однако, этой системе было суждено рано или поздно прийти к конфликту с развивающимся внутри организма матери эмбрио-ном, который несет на себе признаки чужеродности в виде антигенов отца. От агрессии со стороны им-мунной системы матери плод можно было защитить, сократив время его внутриутробного развития, но дополнив его последующим «донашиванием» вне материнского организма, как это происходит у яйце-кладущих и сумчатых животных. Но дальнейшее раз-витие млекопитающих предпочло полное и более длительное развитие плода в организме матери и по-требовало создания таких механизмов регуляции иммунного ответа, которые обеспечивали бы непри-косновенность плода на всем протяжении беремен-ности [1] . Полученные в последние годы данные го-ворят о том, что таких механизмов несколько. Плод как аллотрансплантатВпервые идею о том, что полу-аллогенный плод идентичен аллотрансплантату, частично совпадаю-щему по антигенам главного комплекса гистосовме-стимости (МНС), высказал Питер Медавар в 1953 г.[2]. Антигены МНС матери и отца экспрессируются клетками плода кодоминантно, т.е. в равной степе-ни. Таким образом, если аллели МНС отца полно-стью отсутствуют у матери, 50% этих молекул, унас-ледованные плодом, являются для матери аллоанти-генами. Распознавание отцовских антигенов МНС материнскими Т-лимфоцитами должно приводить к активации последних и отторжению плода. Однако этого не происходит. Более того, отторжения плода не происходит даже в случае его 100% чужеродности, что имеет место при суррогатном материнстве. Ме-давар предположил три различных механизма защи-ты плода от отторжения: 1) существование анатоми-ческого барьера между матерью и плодом; 2) отсу...

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MIC-1 (a multifunctional modulator of dendritic cell phenotype and function) is produced by decidual stromal cells and trophoblasts

Abstract: We have identified MIC-1 as a novel factor (secreted by decidual cells in early pregnancy) that could promote the increase of a tolerogenic subtype of DC in decidua.

Cited by 69 publications

References 42 publications

Human endogenous retrovirus envelope proteins target dendritic cells to suppress T‐cell activation

Human endogenous retrovirus envelope proteins target dendritic cells to suppress T‐cell activation

The CXCL12/CXCR4 axis is involved in the maintenance of Th2 bias at the maternal/fetal interface in early human pregnancy

Mechanisms of maternal tolerance to the fetus: lessons of molecular diplomacy

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