bims-reprim 2021-02-21 papers

Issue of 2021–02–21
five papers selected by
Iva Filipovic, Karolinska Institutet

Front Immunol. 2020 ;11 596489

Gamma/Delta T Cells in the Course of Healthy Human Pregnancy: Cytotoxic Potential and the Tendency of CD8 Expression Make CD56+ γδT Cells a Unique Lymphocyte Subset.

Jasper Nörenberg, Pál Jaksó, Alíz Barakonyi.

To date, pregnancy is an immunological paradox. The semi-allogenic fetus must be accepted by the maternal immune system, while defense against pathogens and immune surveillance cannot be compromised. Gamma/delta T cells are believed to play an important role in this immunological puzzle. In this study, we analyzed peripheral blood CD56+ γδT cells from pregnant women (1st, 2nd, and 3rd trimester) and non-pregnant women by multicolor flow cytometry. Interestingly, γδT cells represent almost half of CD3+/CD56+ cells. Among γδT cells, the CD56+ population expands in the 2nd and 3rd trimester. CD56+ γδT cells maintained a predominantly CD4-/CD8- or CD8+ phenotype, while CD56- γδT cells were in similar rates CD4-/CD8- or CD4+ during pregnancy. Investigation of the lysosomal degranulation marker CD107a revealed a preserved elevated rate of potentially cytotoxic CD56+ γδT cells in pregnancy, while their cytotoxic strength was reduced. Furthermore, CD56+ γδT cells continuously showed a higher prevalence of PD-1 expression. CD56+ γδT cells' rate of PD-1 increased in the 1st trimester and decreased hereafter back to normal level. We correlated the cytotoxic potential and the expression of the inhibitory immune checkpoint PD-1 and were able to demonstrate that highly cytotoxic cells within this CD56+ γδT population tend to express PD-1, which might allow the inhibition of these cells after binding its ligand in the placenta. These findings should support the understanding of the complex processes, which ensure the maintenance of pregnancy.

Keywords: CD4; CD56; CD8; PD-1; cytotoxicity; flow cytometry; gamma/delta T cells; human pregnancy

DOI: https://doi.org/10.3389/fimmu.2020.596489

J Exp Med. 2021 Jan 04. pii: e20202071. [Epub ahead of print]218(1):

Gatekeepers of the fetus: Characterization of placental macrophages.

Christina Megli, Carolyn B Coyne.

In this issue of JEM, Thomas et al. (https://doi.org/10.1084/jem.20200891) provide elegant technological and conceptual advances that further our understanding of the immune cells enriched at the maternal-fetal interface. Using new isolation strategies to better separate maternal- and fetal-derived cells, the authors identify previously undefined maternal-derived immune cells associated with the fetal-derived placenta and provide an in-depth analysis of the markers and characteristics of placental Hofbauer cells.

DOI: https://doi.org/10.1084/jem.20202071

Front Immunol. 2020 ;11 552101

Pregnancy-Induced Changes in microRNA Expression in Multiple Sclerosis.

Helle Bach Søndergaard, Laura Airas, Jeppe Romme Christensen, Birgitte Romme Nielsen, Lars Börnsen, Annette Oturai, Finn Sellebjerg.

Pregnancy affects the disease course in multiple sclerosis (MS), particularly in the third trimester, where the relapse rate is reduced by as much as two thirds. This study aimed at identifying changes in microRNA (miRNA) and immune cell phenotypes in pregnant MS patients. Discovery and validation studies to detect differentially expressed miRNAs were performed with quantitative real-time PCR on peripheral blood mononuclear cells (PBMC). Flow cytometry analysis was performed on PBMC stained with antibodies directed against surface markers of antigen presenting cells (APCs), NK-cells, NKT cells, CD4+ and CD8+ T cells and subsets of these cell types, including PDL1 and PDL2 expressing subsets. RNA was extracted from whole blood, monocytes, and NK-cells to investigate expression and correlation between regulated miRNAs and mRNAs. In total, 15 miRNAs were validated to be differentially expressed between third trimester pregnant and postpartum MS patients (Benjamini-Hochberg false discovery rate from p = 0.03-0.00004). Of these, 12 miRNAs were downregulated in pregnancy and 6 of the 15 miRNAs were altered by more than ±2-fold (+2.99- to -6.38-fold). Pregnant MS patients had a highly significant increase in the percentage of monocytes and a decrease of NK-cells and myeloid dendritic cells compared to non-pregnant MS patients. We confirm previous reports of a relative increase in CD56-bright NK-cells and a decrease in CD56-dim NK-cells in third trimester of pregnancy and report an increase in non-committed follicular helper cells. PDL1 and PDL2 expression was increased in pregnant patients together with IL10. Also, in monocytes IL10, PDL1, and PDL2 were upregulated whereas miR-1, miR-20a, miR-28, miR-95, miR-146a, miR-335, and miR-625 were downregulated between pregnant and untreated MS patients. IL10, PDL1, and PDL2 were predicted targets of MS pregnancy-changed miRNAs, further supported by their negative correlations. Additionally, previously identified pregnancy-regulated mRNAs were identified as predicted targets of the miRNAs. PDL1 and PDL2 bind PD-1 expressed on T cells with an inhibitory effect on T-cell proliferation and increase in IL10 production. These results indicate that some of the effects behind the disease-ameliorating third trimester of pregnancy might be caused by changed expression of miRNAs and immunoregulatory molecules in monocytes.

Keywords: microRNA; multiple sclerosis; postpartum; pregnancy; third trimester

DOI: https://doi.org/10.3389/fimmu.2020.552101

J Clin Invest. 2021 Feb 15. pii: 143137. [Epub ahead of print]131(4):

Ovariectomy induces bone loss via microbial-dependent trafficking of intestinal TNF+ T cells and Th17 cells.

Mingcan Yu, Subhashis Pal, Cameron W Paterson, Jau-Yi Li, Abdul Malik Tyagi, Jonathan Adams, Craig M Coopersmith, M Neale Weitzmann, Roberto Pacifici.

Estrogen deficiency causes a gut microbiome-dependent expansion of BM Th17 cells and TNF-α-producing T cells. The resulting increased BM levels of IL-17a (IL-17) and TNF stimulate RANKL expression and activity, causing bone loss. However, the origin of BM Th17 cells and TNF+ T cells is unknown. Here, we show that ovariectomy (ovx) expanded intestinal Th17 cells and TNF+ T cells, increased their S1P receptor 1-mediated (S1PR1-mediated) egress from the intestine, and enhanced their subsequent influx into the BM through CXCR3- and CCL20-mediated mechanisms. Demonstrating the functional relevance of T cell trafficking, blockade of Th17 cell and TNF+ T cell egress from the gut or their influx into the BM prevented ovx-induced bone loss. Therefore, intestinal T cells are a proximal target of sex steroid deficiency relevant for bone loss. Blockade of intestinal T cell migration may represent a therapeutic strategy for the treatment of postmenopausal bone loss.

Keywords: Bone Biology; Bone disease; Bone marrow; T cells

DOI: https://doi.org/10.1172/JCI143137

Eur J Obstet Gynecol Reprod Biol. 2021 Feb 04. pii: S0301-2115(21)00069-5. [Epub ahead of print]259 38-45

Herpes simplex virus infection in pregnancy - An update.

Wafaa Ali Belail Hammad, Justin C Konje.

Herpes Simplex virus (HSV) infection is one of the most common sexually transmitted infections among women of the reproductive age. It is estimated to affect about 2-3% of pregnant women. Vertical transmission during pregnancy is rare occurring in less than 1% of cases but for those with active lesions or shedding the virus asymptomatically the risk of vertical transmission intrapartum is high. Neonates with HSV may develop severe consequences such as disseminated, central nervous system and skin, eye mouth/mucous disease or suffer mortality. A high index of suspicion, timely diagnosis and institution of appropriate treatment during acute and recurrent episodes will reduce the risk of vertical transmission and therefore neonatal consequences. Routine screening for HSV in pregnancy is not recommended. This review provides an overview of HSV in pregnancy, diagnosis and management especially around unique scenarios such as prelabour preterm rupture of fetal membranes and presentation with active disease in labour.

Keywords: HSV 1 and II; Herpes simplex; Neonatal herpes; Pregnancy; Vertical transmission

DOI: https://doi.org/10.1016/j.ejogrb.2021.01.055