bims-reprim Biomed News
on Reproductive immunology
Issue of 2021–09–12
seven papers selected by
Iva Filipovic, Karolinska Institutet
  1. MAIT Cells Balance the Requirements for Immune Tolerance and Anti-Microbial Defense During Pregnancy.
  2. Mesenchymal stem cells enhance Treg immunosuppressive function at the fetal-maternal interface.
  3. Single-Cell Analysis of the Neonatal Immune System Across the Gestational Age Continuum.
  4. The Inflammatory Feed-Forward Loop Triggered by the Complement Component C3 as a Potential Target in Endometriosis.
  5. Activated γδ T Cells With Higher CD107a Expression and Inflammatory Potential During Early Pregnancy in Patients With Recurrent Spontaneous Abortion.
  6. The induction of preterm labor in rhesus macaques is determined by the  strength of immune response to intrauterine infection.
  7. New treatment target for endometriosis.
  1. Front Immunol. 2021 ;12 718168
    MAIT Cells Balance the Requirements for Immune Tolerance and Anti-Microbial Defense During Pregnancy.
    Johanna Raffetseder, Robert Lindau, Sigrid van der Veen, Göran Berg, Marie Larsson, Jan Ernerudh.
      Mucosal-associated invariant T (MAIT) cells are an innate-like T cell subset with proinflammatory and cytotoxic effector functions. During pregnancy, modulation of the maternal immune system, both at the fetal-maternal interface and systemically, is crucial for a successful outcome and manifests through controlled enhancement of innate and dampening of adaptive responses. Still, immune defenses need to efficiently protect both the mother and the fetus from infection. So far, it is unknown whether MAIT cells are subjected to immunomodulation during pregnancy, and characterization of decidual MAIT cells as well as their functional responses during pregnancy are mainly lacking. We here characterized the presence and phenotype of Vα7.2+CD161+ MAIT cells in blood and decidua (the uterine endometrium during pregnancy) from women pregnant in the 1st trimester, i.e., the time point when local immune tolerance develops. We also assessed the phenotype and functional responses of MAIT cells in blood of women pregnant in the 3rd trimester, i.e., when systemic immunomodulation is most pronounced. Multi-color flow cytometry panels included markers for MAIT subsets, and markers of activation (CD69, HLA-DR, Granzyme B) and immunoregulation (PD-1, CTLA-4). MAIT cells were numerically decreased at the fetal-maternal interface and showed, similar to other T cells in the decidua, increased expression of immune checkpoint markers compared with MAIT cells in blood. During the 3rd trimester, circulating MAIT cells showed a higher expression of CD69 and CD56, and their functional responses to inflammatory (activating anti-CD3/CD28 antibodies, and IL-12 and IL-18) and microbial stimuli (Escherichia coli, group B streptococci and influenza A virus) were generally increased compared with MAIT cells from non-pregnant women, indicating enhanced antimicrobial defenses during pregnancy. Taken together, our findings indicate dual roles for MAIT cells during pregnancy, with an evidently well-adapted ability to balance the requirements of immune tolerance in parallel with maintained antimicrobial defenses. Since MAIT cells are easily activated, they need to be strictly regulated during pregnancy, and failure to do so could contribute to pregnancy complications.
    Keywords:  T cells; anti-microbial response; decidua; immune tolerance; immunomodulation; innate-like T cells; mucosal-associated invariant T (MAIT) cells; pregnancy
    DOI:  https://doi.org/10.3389/fimmu.2021.718168
  2. J Reprod Immunol. 2021 Aug 24. pii: S0165-0378(21)00096-6. [Epub ahead of print]148 103366
    Mesenchymal stem cells enhance Treg immunosuppressive function at the fetal-maternal interface.
    Di Zhang, Yikong Lin, Yunyun Li, Dong Zhao, Meirong Du.
      Well-regulated maternal-fetal immune tolerance is a prerequisite for normal pregnancy. Hyperactivated immune cells and overwhelming inflammatory responses trigger adverse gestation outcome, such as recurrent spontaneous abortion (RSA). Local exacerbation of immunomodulatory cells in maternal decidua is a critical event, tightly linked with fetus acceptance. Owning to the notable immunoregulatory potentials, mesenchymal stromal cells (MSCs) and regulatory T cells (Tregs) have been separately reported as promising therapeutic approaches for refractory RSA attributable to certain immune disorders. However, the cross-talk between MSCs and Tregs at the fetal-maternal interface remains poorly understood. Here we revealed, for the first time, that umbilical MSCs could induce expansion of decidual Foxp3+CD4+ T cells with upregulated production of IL-10 and TGF-β. Meanwhile, MSCs reinforced the immune suppressive functions of decidual Tregs (dTregs). More important, MSCs-instructed dTregs gained enhanced capacity to suppress Th1 and Th17 related inflammatory responses. In vivo data demonstrated that adoptive transfer of MSCs obviously promoted accumulation of Foxp3+ dTregs in lipopolysaccharide (LPS)-induced mice abortion model and spontaneous abortion model (DBA/2-mated female CBA/J mice). Furthermore, MSCs treatment effectively ameliorated absorption rate in both models. This study may offer a new insight for the application of MSCs and Tregs in clinical recurrent miscarriage.
    Keywords:  CD4(+)T cell; Fetal-maternal immune tolerance; MSCs; Pregnancy; Treg
    DOI:  https://doi.org/10.1016/j.jri.2021.103366
  3. Front Immunol. 2021 ;12 714090
    Single-Cell Analysis of the Neonatal Immune System Across the Gestational Age Continuum.
    Laura S Peterson, Julien Hedou, Edward A Ganio, Ina A Stelzer, Dorien Feyaerts, Eliza Harbert, Yamini Adusumelli, Kazuo Ando, Eileen S Tsai, Amy S Tsai, Xiaoyuan Han, Megan Ringle, Pearl Houghteling, Jonathan D Reiss, David B Lewis, Virginia D Winn, Martin S Angst, Nima Aghaeepour, David K Stevenson, Brice Gaudilliere.
      Although most causes of death and morbidity in premature infants are related to immune maladaptation, the premature immune system remains poorly understood. We provide a comprehensive single-cell depiction of the neonatal immune system at birth across the spectrum of viable gestational age (GA), ranging from 25 weeks to term. A mass cytometry immunoassay interrogated all major immune cell subsets, including signaling activity and responsiveness to stimulation. An elastic net model described the relationship between GA and immunome (R=0.85, p=8.75e-14), and unsupervised clustering highlighted previously unrecognized GA-dependent immune dynamics, including decreasing basal MAP-kinase/NFκB signaling in antigen presenting cells; increasing responsiveness of cytotoxic lymphocytes to interferon-α; and decreasing frequency of regulatory and invariant T cells, including NKT-like cells and CD8+CD161+ T cells. Knowledge gained from the analysis of the neonatal immune landscape across GA provides a mechanistic framework to understand the unique susceptibility of preterm infants to both hyper-inflammatory diseases and infections.
    Keywords:  Neonatal immunology; neonatal NK cells; neonatal T cells; neonatal antigen presenting cells; neonatal cytotoxic cells; prematurity
    DOI:  https://doi.org/10.3389/fimmu.2021.714090
  4. Front Immunol. 2021 ;12 693118
    The Inflammatory Feed-Forward Loop Triggered by the Complement Component C3 as a Potential Target in Endometriosis.
    Chiara Agostinis, Sonia Zorzet, Andrea Balduit, Gabriella Zito, Alessandro Mangogna, Paolo Macor, Federico Romano, Miriam Toffoli, Beatrice Belmonte, Gaia Morello, Anna Martorana, Violetta Borelli, Giuseppe Ricci, Uday Kishore, Roberta Bulla.
      The complement system is a major component of humoral innate immunity, acting as a first line of defense against microbes via opsonization and lysis of pathogens. However, novel roles of the complement system in inflammatory and immunological processes, including in cancer, are emerging. Endometriosis (EM), a benign disease characterized by ectopic endometrial implants, shows certain unique features of cancer, such as the capacity to invade surrounding tissues, and in severe cases, metastatic properties. A defective immune surveillance against autologous tissue deposited in the peritoneal cavity allows immune escape for endometriotic lesions. There is evidence that the glandular epithelial cells found in endometriotic implants produce and secrete the complement component C3. Here, we show, using immunofluorescence and RT-qPCR, the presence of locally synthesized C3 in the ectopic endometriotic tissue, but not in the eutopic tissue. We generated a murine model of EM via injection of minced uterine tissue from a donor mouse into the peritoneum of recipient mice. The wild type mice showed greater amount of cyst formation in the peritoneum compared to C3 knock-out mice. Peritoneal washings from the wild type mice with EM showed more degranulated mast cells compared to C3 knock-out mice, consistent with higher C3a levels in the peritoneal fluid of EM patients. We provide evidence that C3a participates in an auto-amplifying loop leading to mast cell infiltration and activation, which is pathogenic in EM. Thus, C3 can be considered a marker of EM and its local synthesis can promote the engraftment of the endometriotic cysts.
    Keywords:  C3; TNF-α; complement system; endometriosis; mast cells
    DOI:  https://doi.org/10.3389/fimmu.2021.693118
  5. Front Immunol. 2021 ;12 724662
    Activated γδ T Cells With Higher CD107a Expression and Inflammatory Potential During Early Pregnancy in Patients With Recurrent Spontaneous Abortion.
    Long Yu, Yang Zhang, Jinfeng Xiong, Jianjun Liu, Ying Zha, Qi Kang, Pan Zhi, Qiang Wang, Hui Wang, Wanjiang Zeng, Yafei Huang.
      Previous studies have reported the involvement of γδ T cells in recurrent spontaneous abortion (RSA); however, both pathogenic and protective effects were suggested. To interrogate the role of γδ T cells in RSA, peripheral blood from RSA patients and healthy women with or without pregnancy were analyzed for γδ T cells by flow cytometry (n = 9-11 for each group). Moreover, the decidua from pregnant RSA patients and healthy controls (RSA-P and HC-P group, respectively) was simultaneously stained for γδ T cells by immunohistochemistry (IHC) and bulk sequenced for gene expression. Our results demonstrated that the frequencies of peripheral γδ T cells and their subpopulations in RSA patients were comparable to that in healthy subjects, but the PD1 expression on Vδ2+ cells was increased in pregnant patients. Furthermore, peripheral Vδ2+ cells in RSA-P patients demonstrated significantly increased expression of CD107a, as compared to that in pregnant healthy controls. In addition, RSA-P patients had higher proportion of IL-17A-secreting but not IL-4-secreting Vδ2+ cells compared to the control groups. In decidua, an inflammatory microenvironment was also evident in RSA-P patients, in which CCL8 expression and the infiltration of certain immune cells were higher than that in the HC-P group, as revealed by transcriptional analysis. Finally, although the presence of γδ T cells in decidua could be detected during pregnancy in both RSA patients and healthy subjects by multicolor IHC analysis, the expression of CD107a on γδ T cells was markedly higher in the RSA-P group. Collectively, our results indicated that the increased activation, cytotoxicity, and inflammatory potential of peripheral and/or local γδ T cells might be responsible for the pathogenesis of RSA. These findings could provide a better understanding of the role of γδ T cells in RSA and shed light on novel treatment strategies by targeting γδ T cells for RSA patients.
    Keywords:  CD107a; IL-17A; PD1; recurrent spontaneous abortion (RSA); γδ T cells
    DOI:  https://doi.org/10.3389/fimmu.2021.724662
  6. PLoS Biol. 2021 Sep 08. 19(9): e3001385
    The induction of preterm labor in rhesus macaques is determined by the  strength of immune response to intrauterine infection.
    Monica Cappelletti, Pietro Presicce, Ma Feiyang, Paranthaman Senthamaraikannan, Lisa A Miller, Matteo Pellegrini, Myung S Sim, Alan H Jobe, Senad Divanovic, Sing Sing Way, Claire A Chougnet, Suhas G Kallapur.
      Intrauterine infection/inflammation (IUI) is a major contributor to preterm labor (PTL). However, IUI does not invariably cause PTL. We hypothesized that quantitative and qualitative differences in immune response exist in subjects with or without PTL. To define the triggers for PTL, we developed rhesus macaque models of IUI driven by lipopolysaccharide (LPS) or live Escherichia coli. PTL did not occur in LPS challenged rhesus macaques, while E. coli-infected animals frequently delivered preterm. Although LPS and live E. coli both caused immune cell infiltration, E. coli-infected animals showed higher levels of inflammatory mediators, particularly interleukin 6 (IL-6) and prostaglandins, in the chorioamnion-decidua and amniotic fluid (AF). Neutrophil infiltration in the chorio-decidua was a common feature to both LPS and E. coli. However, neutrophilic infiltration and IL6 and PTGS2 expression in the amnion was specifically induced by live E. coli. RNA sequencing (RNA-seq) analysis of fetal membranes revealed that specific pathways involved in augmentation of inflammation including type I interferon (IFN) response, chemotaxis, sumoylation, and iron homeostasis were up-regulated in the E. coli group compared to the LPS group. Our data suggest that the intensity of the host immune response to IUI may determine susceptibility to PTL.
    DOI:  https://doi.org/10.1371/journal.pbio.3001385
  7. Nat Rev Endocrinol. 2021 Sep 10.
    New treatment target for endometriosis.
    Claire Greenhill.
      
    DOI:  https://doi.org/10.1038/s41574-021-00564-4
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