Born to be a “Natural Killer”: Understanding the Role of Natural Killer Cells and Galectins in Maternal Immune Response
By: Neha Majety
During pregnancy, a mother’s body undergoes a myriad of changes that are induced and guided by many regulators, some of which include the Galectin family. In the initial stages, the hemochorial placenta must be established, the uterine spiral artery that allows for vascular exchange must be developed and the maternal immune system must be altered. These changes require an immunoprivileged environment with a balance between tolerance to the fetus and defense against pathogens. Understanding the functions of these stakeholders in the process can provide valuable insights on potential players and treatments for type 1 diabetes.
Growing understanding of Galectins
As aforementioned, a mother’s immune response must be altered and regulated in order to prevent fetus rejection during pregnancy. A prior discovery of a subfamily of galectins on chromosome 19 brought to light two such anthropoid primate regulators: Galectin-13 (Gal-13) and Galectin-14 (Gal-14). A group of hungarian researchers further elucidated the role of Gal-13 and Gal-14 on T cell function and their impact on the health of a pregnancy. Results revealed that Gal-13 and Gal-14 were shown to:
- Be expressed during the 1st trimester at the maternal-fetal interface, with decreased expression observed in miscarriage placenta.
- Have activation-dependent T lymphocyte binding, with binding of cytotoxic T cells (Tc) favored over T-helper cells (Th).
- Induce apoptosis in late-apoptotic T lymphocytes, independent of activation status.
- Increase expression of the CD95 T cell activation marker, which mediates apoptotic cell death, while Gal-13 alone increased expression of the CD25 T cell activation marker, which is important for T cell proliferation.
- Overall, their increased expression heightened sensitivity of T cells to Gal-13/Gal-14.
- Induce non-activated T cells to increase production of IL-8, a cytokine that exerts pro-angiogenic effects, suggesting Gal-13/Gal-14 might promote uterine vascularization at the maternal-fetal interface.
Overall, the apoptotic effects on T-cells observed upon Gal-13 and Gal-14 expression reveals the role of the galectins in providing a tolerating immune environment at the maternal-fetal interface. Though these results break ground, more work must be conducted to gain a thorough understanding of the overall impacts of galectins at the interface.
Natural Killer Cells
The hemochorial placenta is a di-compartmental part of the placental organ serving two distinct functions: delivery of maternal nutrients to the placenta and transfer of nutrients to the fetus. During hemochorial placental establishment, natural killer (NK) cells can be directed to the uterine stroma where they are considered regulators in the critical process of uterine spiral artery remodeling – a process necessary for appropriate nutrient and gas exchange. Failures in the remodeling are linked to preeclampsia and miscarriage. A group of Kansas researchers, studied the role of uterine NK cells in a rat model and found that:
- NK cells play a role in regulation of hemochorial placentation.
- NK cells influence uterine spiral artery development, partly explained by their production of proangiogenic factors like vascular or endothelial growth factors (VEGFs).
- Trophoblast stem (TS) cells in a hypoxia environment directed differentiation of an invasive trophoblast phenotype, a process regulated by hypoxia-inducible transcription factors.
- Invasive trophoblast cells led to replacing the endothelium of the arteries.
- Trophoblast lineage decisions were influenced by oxygen tension at the placentation site.
Overall the researchers found that NK cells at healthy levels could restrict and regulate the invasive trophoblast phenotype through its control of hypoxia-induced transcription factors; while the absence of NK cells showed both delayed and poorer uterine spiral artery development.
Another group of researchers studied a subset of NK cells called decidual natural killer (dNK), to better understand the role of antimicrobial peptide granulysin (GNLY) in the balancing act between fetal cell tolerance and defense against infection lead by dNK cells. GNLY is one of many cytotoxic granule proteins dNK cells contain and is highly expressed. In this study, researchers reveal the surprising method by which the placenta is protected from intracellular pathogens finding that:
- dNK cells selectively transferred GNLY, via nanotubes, directly to extravillous trophoblasts (EVTs) containing a pathogenic bacteria – Listeria monocytogenes (Lm) -, resulting in death of the bacteria and trophoblast survival.
- In vitro, GNLY transfer alone strongly inhibited Lm in trophoblast cell lines
These findings were not just restricted to dNK cells, as peripheral NK (pNK) cells also showed GNLY transfer, allowing for host survival concurrent with the death of the pathogen. However, further research on understanding the mechanisms underlying GNLY and the resulting death of the pathogen can highlight methods by which to treat infections during pregnancy.
Why is this important to T1D?
Galectins have been suggested as a potential target by which to limit the T1D autoimmune attack directed by T cells due to their role in inducing T cell apoptosis. Thus, a more comprehensive understanding of their role in the maternal-fetal interface can add to this. Additionally, NK cells serve as a link between adaptive and innate immune systems and have been shown to be in the pancreas of T1D patients. Though their role has been contested as both protective and destructive, understanding their selectivity and the potential role they could play in T1D pathogenesis could reveal players to target.