Low levels of naturally occurring regulatory T lymphocytes in blood of mares with early pregnancy loss

Aurich, Christine; Weber, J.; Nagel, Christina; Merkl, M.; Jude, Rony; Wostmann, Sascha; Ollech, Dirk; Baron, Udo; Olek, Sven; Jansen, Thomas

doi:10.1071/rd13012

Cited by 11 publications

(6 citation statements)

References 46 publications

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“…In humans, Tregs were decreased in peripheral blood and decidua in women with miscarriages and an impaired suppressive capability of Tregs in recurrent miscarriage cases was also observed (Tsuda et al 2019). Furthermore, early pregnancy loss correlated with a low level of naturally occurring Tregs in mares (Aurich et al 2014). Taken together, these observations indicate that equine PSGs, like human and murine PSGs, may play a role in the generation of Tregs via activation of TGFB, and therefore are important to maintain immune tolerance during pregnancy.…”

Section: Discussionmentioning

confidence: 96%

Equine pregnancy-specific glycoprotein CEACAM49 secreted by endometrial cup cells activates TGFB

et al. 2020

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In early equine pregnancy a highly invasive trophoblast cell subpopulation, the chorionic girdle cells, invade the endometrium and form endometrial cups (EC). These cells express classical MHC molecules, thereby stimulating a humoral and cellular immune response, resulting in a massive accumulation of maternal CD4+ and CD8+ T cells around the EC. Nevertheless, no immediate destruction of endometrial cups by maternal lymphoid cells occurs, presumably due to immune tolerance. Although the environment of EC is rich in TGFB and in FOXP3+, CD4+ T cells, the mechanisms leading to tolerance have not been elucidated. Recently, we discovered that equine trophoblast cells secrete pregnancy-specific glycoproteins (PSGs). Since human and murine PSGs activate latent TGFB, we hypothesized that equine PSGs may have a similar activity. We performed plasmon surface resonance experiments to show that equine PSG CEACAM49 can directly bind to the latency-associated peptide (LAP) of both TGFB1 and TGFB2. We then found that the binding of CEACAM49 leads to the activation of TGFB1 as determined by both ELISA and cell-based assays. Furthermore, the activation of TGFB is a unique function of PSGs within the human CEA family, because CEACAM1, 3, 5, 6, 8 do not activate this cytokine. This finding further strengthens the classification of CEACAM49 as an equine PSG. Based on our results, we hypothesize that activation of latent TGFB in the EC environment by equine PSGs secreted by invasive trophoblast cells, could contribute to the generation of regulatory T cells (Tregs) to maintain immune tolerance.

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Section: Discussionmentioning

confidence: 96%

Equine pregnancy-specific glycoprotein CEACAM49 secreted by endometrial cup cells activates TGFB

et al. 2020

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“…In mares, the embryo descends around day 6 to 7 of pregnancy, and implantation starts 10 days later. However, a lower level of peripheral CD4 + FOXP3 + Tregs was noted in mares that experience early pregnancy loss [ 31 ]. A similar phenomenon was observed in women enduring recurrent spontaneous abortion [ 28 ].…”

Section: Discussionmentioning

confidence: 99%

“…The authors suggest two possible hypotheses. First, during the short post-insemination period (24 h), the expansion of uterine Tregs might be limited only to local lymph nodes, or Tregs percentage increases significantly and rapidly only in response to pregnancy, presumably due to fetal antigen and hormone stimulation, as suggested by others [ 5 , 31 , 32 ]. Our results showed that the percentage of CD4 + FOXP3 + lymphocytes is similar during the estrous cycle to that around the endometrial cups, that is, during pregnancy [ 10 ].…”

Section: Discussionmentioning

confidence: 99%

Populations of NK Cells and Regulatory T Cells in the Endometrium of Cycling Mares—A Preliminary Study

Jaworska

Mestre

Wiśniewska

et al. 2022

Animals

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Endometrial immune cells are essential to support uterine functions across the estrous cycle and in preparation for pregnancy. It has been acknowledged that changes in phenotype and/or numbers of lymphocytes, such as regulatory T cells (Tregs) and NK cells, might result in lower fertility in women and mice. Little is known about equine endometrial immune cells across the estrous cycle. Here, we compared the populations of endometrial Tregs and NK cells in estrus and diestrus in mares. Endometrial biopsy and blood samples were taken in estrus and diestrus from 11 mares ages 4–12 years. Flow cytometry with anti-CD4, -CD25 and -FOXP3 and anti-NKp46 and -CD3 antibodies was used to determine the populations of Tregs and NK cells, respectively. The concentration of progesterone was measured with chemiluminescence immunoassay. The results were analyzed with paired Student t tests. The mean percentage of endometrial CD4+FOXP3+ Tregs was 13.7 ± 6.2% in diestrus and 14.5 ± 5.9% in estrus, while the mean percentage of endometrial CD4+FOXP3+CD25+ Tregs changed from 3.6 ± 2.1% in diestrus to 2 ± 2% in estrus (p = 0.0947). The mean proportion of CD3−NKp46+ lymphocytes in the endometrium was not significantly different, with 6 ± 1% in estrus and 6.5 ± 1.4% in diestrus. There was a large variation in the percentage of NK cells between mares of 2.1–12.7%. This study showed, for the first time, the presence of CD4+FOXP3+CD25+ Tregs and CD3−NKp46+ NK cells in the endometrium of non-pregnant cycling mares. The percentage of Tregs, and to a greater extent NK cells, showed large fluctuations between mares. Both Tregs and NK cells might be important for the preparation of the endometrium for semen deposition and pregnancy; however, further research is required.

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“…The infiltrating cells include a higher percentage of FOXP3 + CD4 + T-regulatory cells relative to peripheral blood [ 23 ]. Mares with early pregnancy loss have lower levels of peripheral blood T-regulatory cells [ 22 ]. It is reasonable to hypothesize that memory T-regulatory cells generated in response to our primary transplant ensured early survival of the MHC-I-positive secondary transplant.…”

Section: Discussionmentioning

confidence: 99%

“…Lifespan could be decreased by accelerated immune destruction from a memory response, as observed in serial ectopic transplant studies in mice [ 19 ], or become longer, as observed in male skin grafting experiments in mice in which recipients' immune systems were primed by multiple syngeneic pregnancies [ 20 ]. The latter could occur as a result of regulatory T-lymphocyte memory [ 21 – 23 ] or other mechanisms of induced tolerance, such as T-cell exhaustion resulting from prolonged antigen exposure [ 24 ].…”

Section: Introductionmentioning

confidence: 99%

Ectopic Trophoblast Allografts in the Horse Resist Destruction by Secondary Immune Responses

Brosnahan

Silvela

Crumb

et al. 2016

Biology of Reproduction

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Invasive trophoblast from Day 34 horse conceptuses survives in extrauterine sites in allogeneic recipients that are immunologically naive to donor major histocompatibility complex class I antigens. The ectopic trophoblast retains its in utero characteristics, including similar lifespan, physiologic effect of its secreted product (equine chorionic gonadotropin) upon the recipient's ovaries, and induction of host immune responses. Immunologic memory has not been considered previously in this experimental system. We hypothesized that primary exposure to ectopic trophoblast would affect the recipient's immune status such that the survival time of subsequent transplants would be altered. Secondary transplant lifespans could be shortened by destructive memory responses, as has been observed in ectopic trophoblast studies in rodents, or lengthened, as occurs when male skin grafts follow multiple syngeneic pregnancies in mice. Eight mares received two closely spaced trophoblast transplants. Both grafts for each recipient were obtained from conceptuses sired by the same stallion to provide consistency in histocompatibility antigen exposure. Donor stallions were major histocompatibility complex class I homozygotes. Cytotoxic antibody production was tracked to monitor recipients' immune responses to the transplants. Detection of serum equine chorionic gonadotropin was used as a proxy for transplant lifespan. There was no significant difference between the distributions of primary and secondary transplant lifespans, despite evidence of immunologic memory. These data demonstrate that secondary ectopic trophoblast transplants in horses do not experience earlier destruction or prolonged survival following immune priming of recipients. Mechanisms responsible for the eventual demise of the transplants remain unperturbed by secondary immune responses or chronic antigenic exposure.

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Low levels of naturally occurring regulatory T lymphocytes in blood of mares with early pregnancy loss

Cited by 11 publications

References 46 publications

Equine pregnancy-specific glycoprotein CEACAM49 secreted by endometrial cup cells activates TGFB

Equine pregnancy-specific glycoprotein CEACAM49 secreted by endometrial cup cells activates TGFB

Populations of NK Cells and Regulatory T Cells in the Endometrium of Cycling Mares—A Preliminary Study

Ectopic Trophoblast Allografts in the Horse Resist Destruction by Secondary Immune Responses

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