bims-reprim 2022-03-06 papers

bims-reprim

Biomed News

on Reproductive immunology

Issue of 2022–03–06
six papers selected by
Iva Filipovic, Karolinska Institutet

Establishment of fetomaternal tolerance through glycan-mediated B cell suppression.
Mapping the non-pregnant uterus cell-by-cell.
Next generation of immune checkpoint molecules in maternal-fetal immunity.
Decidual immune response following COVID-19 during pregnancy varies by timing of maternal SARS-CoV-2 infection.
An imbalance of the IL-33/ST2-AXL-efferocytosis axis induces pregnancy loss through metabolic reprogramming of decidual macrophages.
CD39/CD73 Dysregulation of Adenosine Metabolism Increases Decidual Natural Killer Cell Cytotoxicity: Implications in Unexplained Recurrent Spontaneous Abortion.

Nature. 2022 Mar 02.

Establishment of fetomaternal tolerance through glycan-mediated B cell suppression.

G Rizzuto, J F Brooks, S T Tuomivaara, T I McIntyre, S Ma, D Rideaux, J Zikherman, S J Fisher, A Erlebacher.

Discrimination of self from non-self is fundamental to a wide range of immunological processes1. During pregnancy, the mother does not recognize the placenta as immunologically foreign because antigens expressed by trophoblasts, the placental cells that interface with the maternal immune system, do not activate maternal T cells2. Currently, these activation defects are thought to reflect suppression by regulatory T cells3. By contrast, mechanisms of B cell tolerance to trophoblast antigens have not been identified. Here we provide evidence that glycan-mediated B cell suppression has a key role in establishing fetomaternal tolerance in mice. B cells specific for a model trophoblast antigen are strongly suppressed through CD22-LYN inhibitory signalling, which in turn implicates the sialylated glycans of the antigen as key suppressive determinants. Moreover, B cells mediate the MHC-class-II-restricted presentation of antigens to CD4+ T cells, which leads to T cell suppression, and trophoblast-derived sialoglycoproteins are released into the maternal circulation during pregnancy in mice and humans. How protein glycosylation promotes non-immunogenic placental self-recognition may have relevance to immune-mediated pregnancy complications and to tumour immune evasion. We also anticipate that our findings will bolster efforts to harness glycan biology to control antigen-specific immune responses in autoimmune disease.

DOI: https://doi.org/10.1038/s41586-022-04471-0
Dev Cell. 2022 02 28. pii: S1534-5807(22)00075-2. [Epub ahead of print]57(4): 421-423

Mapping the non-pregnant uterus cell-by-cell.

Aleksandra O Tsolova, Varsha Jain, Hilary O D Critchley.

The endometrium is a dynamic, multicellular tissue that is constantly remodeled in response to regulating hormones. In a recent issue of Nature Genetics, Garcia-Alonso et al. delineate the unique genetic signatures of the endometrial cells. Their findings validate a three-dimensional epithelial organoid system for modeling endometrial glands ex utero.

DOI: https://doi.org/10.1016/j.devcel.2022.02.009
Immunol Rev. 2022 Mar 02.

Next generation of immune checkpoint molecules in maternal-fetal immunity.

Si-Jia Zhao, Kahindo P Muyayalo, Jing Luo, Donghui Huang, Gil Mor, Ai-Hua Liao.

  Successful pregnancy is a unique situation requires the maternal immune system to recognize and tolerate a semi-identical fetus and allow normal invasion of trophoblast cells. Although efforts have been made, the deep mechanisms of the maternal-fetal crosstalk have not yet been fully deciphered. Immune checkpoint molecules (ICMs) are a group of negative modulators of the immune response that avoid immune damage. They have been extensively studied in the fields of oncology and transplantation, while the latest evidence suggests that they are closely associated with pregnancy outcomes via multiple inhibitory mechanisms. Although studies have mostly demonstrated the regulatory role of the well-known PD-1, CTLA-4 at the maternal-fetal interface, what is unique about the newly discovered multiple ICMs remains a mystery. Here, we review the latest knowledge on ICMs, focusing on the first generation of checkpoints (PD-1, CTLA-4) and the next generation (Tim-3, Tigit, Lag-3, VISTA) highlighting their immunoregulatory roles in maternal-fetal tolerance and decidual vascular remodeling, and their involvement in pathological pregnancies. The content covers three aspects: the characteristics they possess, the dynamic expression profile of their expression at the maternal-fetal interface, and their involvement in pathological pregnancy. In immunotherapy strategies for pregnancy complications, upregulation of immune checkpoints may play a role. Meanwhile, the impact on pregnancy outcomes when using ICMs in clinical cancer treatment during pregnancy is a topic worth exploring. These may serve as a guide for future basic research and clinical applications of maternal-fetal immunity.

Keywords:  CTLA-4; Lag-3; PD-1; Tigit; Tim-3; VISTA; maternal-fetal immunity; pregnancy

DOI:  https://doi.org/10.1111/imr.13073
J Reprod Immunol. 2022 Feb 24. pii: S0165-0378(22)00030-4. [Epub ahead of print]151 103501

Decidual immune response following COVID-19 during pregnancy varies by timing of maternal SARS-CoV-2 infection.

Lillian J Juttukonda, Elisha M Wachman, Jeffery Boateng, Mayuri Jain, Yoel Benarroch, Elizabeth S Taglauer.

  While COVID-19 infection during pregnancy is common, fetal transmission is rare, suggesting that intrauterine mechanisms form an effective blockade against SARS-CoV-2. Key among these is the decidual immune environment of the placenta. We hypothesize that decidual leukocytes are altered by maternal SARS-CoV-2 infection in pregnancy and that this decidual immune response is shaped by the timing of infection during gestation. To address this hypothesis, we collected decidua basalis tissues at delivery from women with symptomatic COVID-19 during second (2nd Tri COVID, n = 8) or third trimester (3rd Tri COVID, n = 8) and SARS-CoV-2-negative controls (Control, n = 8). Decidual natural killer (NK) cells, macrophages and T cells were evaluated using quantitative microscopy, and pro- and anti-inflammatory cytokine mRNA expression was evaluated using quantitative reverse transcriptase PCR (qRT-PCR). When compared with the Control group, decidual tissues from 3rd Tri COVID exhibited significantly increased macrophages, NK cells and T cells, whereas 2nd Tri COVID only had significantly increased T cells. In evaluating decidual cytokine expression, we noted that IL-6, IL-8, IL-10 and TNF-α were significantly correlated with macrophage cell abundance. However, in 2nd Tri COVID tissues, there was significant downregulation of IL-6, IL-8, IL-10, and TNF-α. Taken together, these results suggest innate and adaptive immune responses are present at the maternal-fetal interface in maternal SARS-CoV-2 infections late in pregnancy, and that infections earlier in pregnancy show evidence of a resolving immune response. Further studies are warranted to characterize the full scope of intrauterine immune responses in pregnancies affected by maternal COVID-19.

Keywords:  COVID-19 in pregnancy; Cytokines; Decidual leukocytes; SARS-CoV-2; Vertical transmission

DOI:  https://doi.org/10.1016/j.jri.2022.103501
Cell Mol Life Sci. 2022 Mar 04. 79(3): 173

An imbalance of the IL-33/ST2-AXL-efferocytosis axis induces pregnancy loss through metabolic reprogramming of decidual macrophages.

Yan-Ran Sheng, Wen-Ting Hu, Hui-Hui Shen, Chun-Yan Wei, Yu-Kai Liu, Xiao-Qian Ma, Ming-Qing Li, Xiao-Yong Zhu.

  During embryo implantation, apoptosis is inevitable. These apoptotic cells (ACs) are removed by efferocytosis, in which macrophages are filled with a metabolite load nearly equal to the phagocyte itself. A timely question pertains to the relationship between efferocytosis-related metabolism and the immune behavior of decidual macrophages (dMΦs) and its effect on pregnancy outcome. Here, we report positive feedback of IL-33/ST2-AXL-efferocytosis leading to pregnancy failure through metabolic reprogramming of dMΦs. We compared the serum levels of IL-33 and sST2, along with IL-33 and ST2, efferocytosis and metabolism of dMΦs, from patients with normal pregnancies and unexplained recurrent pregnancy loss (RPL). We revealed disruption of the IL-33/ST2 axis, increased apoptotic cells and elevated efferocytosis of dMΦs from patients with RPL. The dMΦs that engulfed many apoptotic cells secreted more sST2 and less TGF-β, which polarized dMΦs toward the M1 phenotype. Moreover, the elevated sST2 biased the efferocytosis-related metabolism of RPL dMΦs toward oxidative phosphorylation and exacerbated the disruption of the IL-33/ST2 signaling pathway. Metabolic disorders also lead to dysfunction of efferocytosis, resulting in more uncleared apoptotic cells and secondary necrosis. We also screened the efferocytotic molecule AXL regulated by IL-33/ST2. This positive feedback axis of IL-33/ST2-AXL-efferocytosis led to pregnancy failure. IL-33 knockout mice demonstrated poor pregnancy outcomes, and exogenous supplementation with mouse IL-33 reduced the embryo losses. These findings highlight a new etiological mechanism whereby dMΦs leverage immunometabolism for homeostasis of the microenvironment at the maternal-fetal interface.

Keywords:  Decidual macrophages; Efferocytosis; IL-33/ST2 axis; Metabolic immune reprogramming; Recurrent pregnancy loss

DOI:  https://doi.org/10.1007/s00018-022-04197-2
Front Immunol. 2022 ;13 813218

CD39/CD73 Dysregulation of Adenosine Metabolism Increases Decidual Natural Killer Cell Cytotoxicity: Implications in Unexplained Recurrent Spontaneous Abortion.

Jianan Zhu, Guangmin Song, Xiaobo Zhou, Ting-Li Han, Xinyang Yu, Hao Chen, Toby Mansell, Boris Novakovic, Philip N Baker, Richard D Cannon, Richard Saffery, Chang Chen, Hua Zhang.

  Unexplained recurrent spontaneous abortion (URSA) is believed to be associated with impaired immunosuppression at the maternal-fetal interface, but the detailed molecular mechanism remains unclear. The ATP-adenosine metabolic pathway regulated by CD39/CD73 has recently been recognized to be important in immunosuppression. This study aimed to investigate the regulation of decidual natural killer (dNK) cells and fetal extravillous trophoblast (EVT) cells by CD39 and CD73 in URSA, as well as the possible regulatory mechanism of CD39/CD73 via the TGF-β-mTOR-HIF-1α pathway using clinical samples and cell models. Fewer CD39+ and CD73+ cells were found in the URSA decidual and villous tissue, respectively. Inhibition of CD39 on dNK cells transformed the cells to an activated state with increased toxicity and decreased apoptosis, and changed their cytokine secretion, leading to impaired invasion and proliferation of the co-cultured HTR8/SVneo cells. Similarly, inhibition of CD73 on HTR8/SVneo cells decreased the adenosine concentration in the cell culture media, increased the proportion of CD107a+ dNK cells, and decreased the invasion and proliferation capabilities of the HTR8/SVneo cells. In addition, transforming growth factor-β (TGF-β) triggered phosphorylation of mammalian target of rapamycin (mTOR) and Smad2/Smad3, which subsequently activated hypoxia-inducible factor-1α (HIF-1α) to induce the CD73 expression on the HTR8/SVneo cells. In summary, reduced numbers of CD39+ and CD73+ cells at the maternal-fetal interface, which may be due to downregulated TGF-β-mTOR-HIF-1α pathway, results in reduced ATP-adenosine metabolism and increased dNK cytotoxicity, and potentially contributes to URSA occurrences.

Keywords:  CD39; CD73; TGF-β; URSA; adenosine; dNK

DOI:  https://doi.org/10.3389/fimmu.2022.813218