Single-cell analysis of the aged ovarian immune system reveals a shift towards adaptive immunity and attenuated cell function
- Technion - Israel Institute of Technology, Israel
Abstract
The immune system plays a major role in maintaining many physiological processes in the reproductive system. However, a complete characterization of the immune milieu in the ovary, and particularly how it is affected by female aging, is still lacking. Here, we utilize single-cell RNA sequencing and flow cytometry to construct the complete description of the murine ovarian immune system. We show that the composition of the immune cells undergoes an extensive shift with age towards adaptive immunity. We analyze the effect of aging on gene expression and chemokine and cytokine networks and show an overall decreased expression of inflammatory mediators together with an increased expression of senescent cells recognition receptors. Our results suggest that the fertile female's ovarian immune aging differs from the suggested female post-menopause inflammaging as it copes with the inflammatory stimulations during repeated cycles and the increasing need for clearance of accumulating atretic follicles.
Data availability
All data used in this study are included in the manuscript, the supporting files and in GitHub:https://github.com/SavirLab/AgingOvarianImmuneMilieu
Article and author information
Author details
Funding
Israel Science Foundation (1619/20)
- Tal Ben Yaakov
- Tanya Wasserman
- Eliel Aknin
- Yonatan Savir
Rappaport Family Institute for Research in the Medical Sciences
- Tal Ben Yaakov
- Tanya Wasserman
- Eliel Aknin
- Yonatan Savir
Wolfson Foundation
- Tal Ben Yaakov
- Tanya Wasserman
- Eliel Aknin
- Yonatan Savir
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.This work is supported by the Rappaport Family Institute for Research in the Medical Sciences (YS), the Russell Berrie Nanotechnology Institute (YS), UOM-Israel collaboration (YS), The Wolfson Foundation (YS), ISF grant 1860/21 (RH).
Reviewing Editor
- Sara Hägg, Karolinska Institutet, Sweden
Ethics
Animal experimentation: All mouse experiments performed in this study were approved by the Animal Care and UseCommittee of the Technion, Israel Institute of Technology, and found to confirm with theregulations of this Institution for work with laboratory animals, protocol No: IL-069-05-2021.
Version history
- Preprint posted: August 13, 2021 (view preprint)
- Received: October 21, 2021
- Accepted: April 19, 2023
- Accepted Manuscript published: April 25, 2023 (version 1)
- Version of Record published: May 16, 2023 (version 2)
Copyright
© 2023, Ben Yaakov et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Single-cell analysis of the aged ovarian immune system reveals a shift towards adaptive immunity and attenuated cell function
eLife 12:e74915.
https://doi.org/10.7554/eLife.74915
Further reading
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Accurate prediction of the structurally diverse complementarity determining region heavy chain 3 (CDR-H3) loop structure remains a primary and long-standing challenge for antibody modeling. Here, we present the H3-OPT toolkit for predicting the 3D structures of monoclonal antibodies and nanobodies. H3-OPT combines the strengths of AlphaFold2 with a pre-trained protein language model and provides a 2.24 Å average RMSDCα between predicted and experimentally determined CDR-H3 loops, thus outperforming other current computational methods in our non-redundant high-quality dataset. The model was validated by experimentally solving three structures of anti-VEGF nanobodies predicted by H3-OPT. We examined the potential applications of H3-OPT through analyzing antibody surface properties and antibody–antigen interactions. This structural prediction tool can be used to optimize antibody–antigen binding and engineer therapeutic antibodies with biophysical properties for specialized drug administration route.
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Background:
Preterm birth is the leading cause of neonatal morbidity and mortality worldwide. Most cases of preterm birth occur spontaneously and result from preterm labor with intact (spontaneous preterm labor [sPTL]) or ruptured (preterm prelabor rupture of membranes [PPROM]) membranes. The prediction of spontaneous preterm birth (sPTB) remains underpowered due to its syndromic nature and the dearth of independent analyses of the vaginal host immune response. Thus, we conducted the largest longitudinal investigation targeting vaginal immune mediators, referred to herein as the immunoproteome, in a population at high risk for sPTB.
Methods:
Vaginal swabs were collected across gestation from pregnant women who ultimately underwent term birth, sPTL, or PPROM. Cytokines, chemokines, growth factors, and antimicrobial peptides in the samples were quantified via specific and sensitive immunoassays. Predictive models were constructed from immune mediator concentrations.
Results:
Throughout uncomplicated gestation, the vaginal immunoproteome harbors a cytokine network with a homeostatic profile. Yet, the vaginal immunoproteome is skewed toward a pro-inflammatory state in pregnant women who ultimately experience sPTL and PPROM. Such an inflammatory profile includes increased monocyte chemoattractants, cytokines indicative of macrophage and T-cell activation, and reduced antimicrobial proteins/peptides. The vaginal immunoproteome has improved predictive value over maternal characteristics alone for identifying women at risk for early (<34 weeks) sPTB.
Conclusions:
The vaginal immunoproteome undergoes homeostatic changes throughout gestation and deviations from this shift are associated with sPTB. Furthermore, the vaginal immunoproteome can be leveraged as a potential biomarker for early sPTB, a subset of sPTB associated with extremely adverse neonatal outcomes.
Funding:
This research was conducted by the Perinatology Research Branch, Division of Obstetrics and Maternal-Fetal Medicine, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, U.S. Department of Health and Human Services (NICHD/NIH/DHHS) under contract HHSN275201300006C. ALT, KRT, and NGL were supported by the Wayne State University Perinatal Initiative in Maternal, Perinatal and Child Health.
