Cellular senescence induced by CD158d reprograms natural killer cells to promote vascular remodeling
Open accessAbstract
Natural killer (NK) cells, which have an essential role in immune defense, also contribute to reproductive success. NK cells are abundant at the maternal–fetal interface, where soluble HLA-G is produced by fetal trophoblast cells during early pregnancy. Soluble HLA-G induces a proinflammatory response in primary, resting NK cells on endocytosis into early endosomes where its receptor, CD158d, resides. CD158d initiates signaling through DNA-PKcs, Akt, and NF-κB for a proinflammatory and proangiogenic response. The physiological relevance of this endosomal signaling pathway, and how activation of CD158d through soluble ligands regulates NK cell fate and function is unknown. We show here that CD158d agonists trigger a DNA damage response signaling pathway involving cyclin-dependent kinase inhibitor p21 expression and heterochromatin protein HP1-γ phosphorylation. Sustained activation through CD158d induced morphological changes in NK cell shape and size, and survival in the absence of cell-cycle entry, all hallmarks of senescence, and a transcriptional signature of a senescence-associated secretory phenotype (SASP). SASP is a program that can be induced by oncogenes or DNA damage, and promotes growth arrest and tissue repair. The secretome of CD158d-stimulated senescent NK cells promoted vascular remodeling and angiogenesis as assessed by functional readouts of vascular permeability and endothelial cell tube formation. Retrospective analysis of the decidual NK cell transcriptome revealed a strong senescence signature. We propose that a positive function of senescence in healthy tissue is to favor reproduction through the sustained activation of NK cells to remodel maternal vasculature in early pregnancy.
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Trophoblast senescence is physiological, progresses with gestation and peaks at term; senescence is also described in maternal decidual cells and fetoplacental membranes, where it promotes parturition and placental detachment at term.
“In addition to trophoblast senescence, which is a physiological phenomenon that progresses with gestation and peaks at term, senescence is also extensively described in maternal decidual cells and fetoplacental membranes, where it has a pivotal role in the promotion of parturition and detachment of the placenta from the uterus at term257–262.”
From SenNet recommendations for detecting senescent cells in different tissues (2024) · cites this paper as [262]
The section on CD158d activation reports a senescence signature in decidual NK cells during weeks 6–12 of pregnancy, and the paper proposes a reproductive role through vascular remodeling in early pregnancy. It does not establish senescence of trophoblasts or fetoplacental membranes, progression or a peak at term, or a role in parturition or placental detachment. (LLM, conf=0.84)
Experimental — accuracy not yet measuredCellular senescence has physiological roles during development, in adult megakaryocytes, syncytiotrophoblasts, wound healing and placental natural killer lymphocytes.
“Apart from its beneficial role as an anti-tumour response, physiological roles for cellular senescence have also been identified during development [15,16], in adult megakaryocytes, syncytiotrophoblasts, wound healing and placental natural killer lymphocytes [17,18,19].”
From Ageing, Cellular Senescence and Neurodegenerative Disease (2018) · cites this paper as [19]
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- Authors
- Rajagopalan, S., & Long, E. O.
- Affiliations
- National Institute of Allergy and Infectious Diseases (US)
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2012-11-26
- Volume
- 109
- Issue
- 50
- Pages
- 20596-20601
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC3528503
- OpenAlex
- W2018476521
- Cited by
- 168
- References
- 12
- Citations by year
- 2026: 9 · 2025: 9 · 2024: 7 · 2023: 13 · 2022: 11 · 2021: 18 · 2020: 18 · 2019: 12 · 2018: 16 · 2017: 15 · 2016: 7 · 2015: 11 · 2014: 18 · 2013: 4
- FWCI
- 4.60
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- National Institute of Allergy and Infectious Diseases
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Immune Cell Function and Interaction
- Life Sciences › Immunology and Microbiology › Immunology › Reproductive System and Pregnancy
- Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
- Keywords
- cellular senescence, natural killer cells, soluble HLA-G, maternal-fetal interface, decidual NK cells, vascular remodeling, angiogenesis, senescence-associated secretory phenotype, DNA damage response, p21, NF-κB signaling, DNA-PKcs, Akt signaling, pregnancy
- MeSH terms
- Blood Vessels, Capillary Permeability, Cells, Cultured, Chromosomal Proteins, Non-Histone, DNA Damage, Female, Humans, Killer Cells, Natural, Maternal-Fetal Exchange, Phosphorylation, Pregnancy, Signal Transduction, Cellular Senescence, Neovascularization, Physiologic, Cyclin-Dependent Kinase Inhibitor p21, Receptors, KIR2DL4, HLA-G Antigens
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