Tolerance Signaling Molecules and Pregnancy: IDO, Galectins, and the Renaissance of Regulatory T Cells

Terness, Peter; Kallikourdis, Marinos; Betz, Alexander G.; Rabinovich, Gabriel A.; Saito, Shigeru; Clark, David A.

doi:10.1111/j.1600-0897.2007.00510.x

Cited by 110 publications

(80 citation statements)

References 151 publications

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“…An example of compromised recognition of SCNT conceptuses by the endometrium is the gene encoding the enzyme indoleamine 2,3-dioxygenase-1 (IDO1), which is down-regulated in caruncular tissue (fold change, 0.54; FDR < 0.05) and also tended to be down-regulated in intercaruncular tissue (fold change, 0.67; FDR = 0.08). IDO1 is one of the enzymes responsible for catabolizing tryptophan in a pathway essential for maternal immune tolerance toward the conceptus (37,38). Down-regulation of IDO1 may be directly linked to the reduced likelihood of implantation success in cloned conceptuses.…”

Section: Discussionmentioning

confidence: 99%

Massive dysregulation of genes involved in cell signaling and placental development in cloned cattle conceptus and maternal endometrium

Biase

Rabel

Guillomot

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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A major unresolved issue in the cloning of mammals by somatic cell nuclear transfer (SCNT) is the mechanism by which the process fails after embryos are transferred to the uterus of recipients before or during the implantation window. We investigated this problem by using RNA sequencing (RNA-seq) to compare the transcriptomes in cattle conceptuses produced by SCNT and artificial insemination (AI) at day (d) 18 (preimplantation) and d 34 (postimplantation) of gestation. In addition, endometrium was profiled to identify the communication pathways that might be affected by the presence of a cloned conceptus, ultimately leading to mortality before or during the implantation window. At d 18, the effects on the transcriptome associated with SCNT were massive, involving more than 5,000 differentially expressed genes (DEGs). Among them are 121 genes that have embryonic lethal phenotypes in mice, cause defects in trophoblast and placental development, and/or affect conceptus survival in mice. In endometria at d 18, <0.4% of expressed genes were affected by the presence of a cloned conceptus, whereas at d 34, ∼36% and <0.7% of genes were differentially expressed in intercaruncular and caruncular tissues, respectively. Functional analysis of DEGs in placental and endometrial tissues suggests a major disruption of signaling between the cloned conceptus and the endometrium, particularly the intercaruncular tissue. Our results support a "bottleneck" model for cloned conceptus survival during the periimplantation period determined by gene expression levels in extraembryonic tissues and the endometrial response to altered signaling from clones. somatic cell nuclear transfer | conceptus | placentation | conceptus-maternal communication I n cattle, as in other mammals, exquisitely orchestrated physiological changes of the conceptus and uterus are necessary for a successful pregnancy. Synchronization of the complex events at the time of implantation relies on the timed release of molecular signals from the conceptus and the endometrium. Embryo-derived IFN-τ (IFNT) is the major signal of pregnancy in cattle, preventing luteolysis and regulating the expression of genes that are responsible for promoting local changes in the endometrium to accommodate the conceptus (1-3). In females, progesterone is the major driver of endometrial changes that prepare the uterus for conceptus implantation (4, 5). In addition to IFNT and progesterone, signaling between the bovine conceptus and the endometrium is bidirectional, and involves several pathways that work concomitantly (6) for the successful establishment of pregnancy.Independent studies have shown that the majority of embryonic losses in cattle occur during the period that spans embryo cleavage until the attachment of the blastocyst to the endometrium (7). The reasons for these losses remain unclear and likely result from several factors, including embryonic lethal genes (8, 9), environmental stressors (7), and endometrial condition (10). Cloning of cattle by somatic cell nuclear transfer ...

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Section: Discussionmentioning

confidence: 99%

Massive dysregulation of genes involved in cell signaling and placental development in cloned cattle conceptus and maternal endometrium

Biase

Rabel

Guillomot

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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“…Adenosine can bind to its receptor A2A expressed on T eff cells to suppress their responses. Additionally, it has been suggested that several members of the galectin family of carbohydrate-binding proteins are involved in T reg cell function [59][60][61] . It has also been proposed that another cytokine, IL-35, is responsible for close-range suppression by T reg cells.…”

Section: T Reg Cell-derived Suppressor Moleculesmentioning

confidence: 99%

The Foxp3+ regulatory T cell: a jack of all trades, master of regulation

2008

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The function of regulatory T cells (T reg cells) has been attributed to a growing number of diverse pathways, molecules and processes. Seemingly contradictory conclusions regarding the mechanisms underlying T reg cell suppressive activity have revitalized skeptics in the field who challenge the core validity of the idea of T reg cells as central immune regulators. However, we note that a consensus may be emerging from the data: that multiple T reg cell functions act either directly or indirectly at the site of antigen presentation to create a regulatory milieu that promotes bystander suppression and infectious tolerance. Thus, the versatility and adaptability of the Foxp3 + T reg cells may in fact be the best argument that these cells are 'multitalented masters of immune regulation'.Armed with the potential to destroy invading microorganisms and stop aberrant outgrowth of tumor cells, the immune system has extensive built-in mechanisms for preventing attack of healthy self tissues. The first line of such 'self-tolerance' is the elimination of selfreactive T lymphocytes and B lymphocytes during negative selection in the thymus and bone marrow, respectively. However, there has long been a belief that the immune system must have peripheral mechanisms in place to deal with immune cells that 'escape' central tolerance. For almost 40 years, immunologists have postulated the existence of suppressor T cells that police the immune system to avert unwanted immune responses 1-3 . However, that phenomenology was cast into doubt as various labs presented unique, hard-to-reproduce systems, each with complexities and idiosyncrasies that raised credibility issues. This situation was not unlike the early years of cytokine biology, during which dozens of activities were found in sera and cell supernatants without consistent molecular or biochemical 'signatures'. Fortunately, as biochemistry and the molecular biology revolution rescued the field of cytokine biology by identifying genes and biochemical structures tied to the varied biologic activities, the identification of a constellation of cell surface, transcriptional and biochemical markers that uniquely mark 'regulatory' T cells (T reg cells) has made possible a rebirth of the suppressor T cell field over the past decade.The realization that T reg cells have a unique surface expression profile incorporating CD25, CD62L and specific CD45 isoforms 4-6 , together with the identification of the T reg cellspecific transcription factor Foxp3, catapulted T reg cells from a rare CD4 + T cell subset to

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“…In humans, the decidualization process involves the transformation of stromal fibroblasts into epithelioid decidual cells and the recruitment of immune cells critical for decidual development in an early inflammatory microenvironment; thus, multiple regulatory mechanisms are required to maintain the local immune homeostasis (Wilcox et al 1999, Terness et al 2007, Chaouat et al 2010, Yoshinaga 2010.…”

Section: Discussionmentioning

confidence: 99%

“…In this context, Nancy et al (2012) recently reported that genes encoding chemokines are subject to epigenetic silencing in decidual stromal cells to restrain the attraction of Th1 and T cytotoxic profiles as a strategy to prevent potential tissue damage. In brief, the decidualization program involves many regulatory molecules that play functional roles, such as insulin-like growth factors, interleukin 1, 6, 10 and TGFb families, the neuropeptide VIP, chemokines such as RANTES with their receptors and adhesion molecules that generate a network to control implantation processes such as trophoblast adhesion, invasion and the selective recruitment of maternal leukocyte subpopulations (Salamonsen & Woolley 1999, Dimitriadis et al 2010, Terness et al 2007, Yoshinaga 2010, Fraccaroli et al 2011.…”

Section: Ccr7mentioning

confidence: 99%

VIP contribution to the decidualization program: regulatory T cell recruitment

Grasso¹,

Paparini²,

Agüero³

et al. 2014

Journal of Endocrinology

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During early pregnancy, the human uterus undergoes profound tissue remodeling characterized by leukocyte invasion and production of proinflammatory cytokines, followed by tissue repair and tolerance maintenance induction. Vasoactive intestinal peptide (VIP) is produced by trophoblast cells and modulates the maternal immune response toward a tolerogenic profile. Here, we evaluated the contribution of the VIP/VPAC to endometrial renewal, inducing decidualization and the recruitment of induced regulatory T cells (iTregs) that accompany the implantation period. For that purpose, we used an in vitro model of decidualization with a human endometrial stromal cell line (HESC) stimulated with progesterone (P 4 ) and lipopolysaccharide (LPS) simulating the inflammatory response during implantation and human iTregs (CD4) differentiated from naïve T cells obtained from peripheral blood mononuclear cells of fertile women. We observed that VIP and its receptor VPAC1 are constitutively expressed in HESCs and that P 4 increased VIP expression. Moreover, in HESC VIP induced expression of RANTES (CCL5), one of the main chemokines involved in T cell recruitment, and this effect is enhanced by the presence of P 4 and LPS. Finally, assays of the migration of iTregs toward conditioned media from HESCs revealed that endogenous VIP production induced by P 4 and LPS and RANTES production were involved, as anti-RANTES neutralizing Ab or VIP antagonist prevented their migration. We conclude that VIP may have an active role in the decidualization process, thus contributing to recruitment of iTregs toward endometrial stromal cells by increasing RANTES expression in a P 4 -dependent manner.

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Tolerance Signaling Molecules and Pregnancy: IDO, Galectins, and the Renaissance of Regulatory T Cells

Cited by 110 publications

References 151 publications

Massive dysregulation of genes involved in cell signaling and placental development in cloned cattle conceptus and maternal endometrium

Massive dysregulation of genes involved in cell signaling and placental development in cloned cattle conceptus and maternal endometrium

The Foxp3+ regulatory T cell: a jack of all trades, master of regulation

VIP contribution to the decidualization program: regulatory T cell recruitment

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