Apoptotic Receptors and CD107a Expression by NK Cells in an Interaction Model with Trophoblast Cells
Valentina A Mikhailova1, Dmitry I Sokolov1,2, Polina V Grebenkina1,2
1FSBSI "The Research Institute of Obstetrics Gynecology and Reproductology Named after D.O.Ott", 199034 Saint-Petersburg, Russia.
Abstract:
Natural killer cells (NK cells) exert cytotoxicity towards target cells in several ways, including the expression of apoptosis-mediating ligands (TRAIL, FasL). In addition, NK cells themselves may be susceptible to apoptosis due to the expression of TRAIL receptors. These receptors include TRAIL-R1 (DR4), TRAIL-R2 (DR5), capable of inducing apoptosis, and TRAIL-R3 (DcR1), TRAIL-R4 (DcR2), the so-called "decoy receptors", which lack an intracellular domain initiating activation of caspases. Of particular interest is the interaction of uterine NK cells with cells of fetal origin, trophoblasts, which are potential targets for natural killer cells to carry out cytotoxicity. The aim of this work was to evaluate the expression of proapoptotic receptors and their ligands as well as CD107a expression by NK cells in a model of interaction with trophoblast cells. To evaluate NK cells, we used cells of the NK-92 line; cells of the JEG-3 line were used as target cells. The cytokines IL-1β, IL-15, IL-18, TNFα, IL-10, TGFβ and conditioned media (CM) of the first and third trimester chorionic villi explants were used as inducers. We established that cytokines changed the expression of apoptotic receptors by NK cells: in the presence of TNFα, the amount and intensity of Fas expression increased, while in the presence of TGFβ, the amount and intensity of expression of the DR5 receptor decreased. Soluble chorionic villi factors alter the expression of TRAIL and FasL by NK-92 cells, which can reflect the suppression of the TRAIL-dependent mechanism of apoptosis in the first trimester and stimulating the Fas-dependent mechanism in the third trimester. In the presence of trophoblast cells, the expression of TRAIL and DcR1 by NK cells was reduced compared to intact cells, indicating an inhibitory effect of trophoblast cells on NK cell cytotoxicity. In the presence of chorionic villi CM and trophoblast cells, a reduced number of NK-92 cells expressing DR4 and DR5 was found. Therefore, soluble factors secreted by chorionic villi cells regulate the resistance of NK cells to death by binding TRAIL, likely maintaining their activity at a certain level in case of contact with trophoblast cells.
Insights
Natural killer (NK) cells interact with trophoblasts, influencing apoptosis pathways. Soluble factors from chorionic villi modulate NK cell receptor expression, potentially regulating their cytotoxic activity during pregnancy.
Area of Science:
- Immunology
- Reproductive Biology
- Cell Biology
Background:
- Natural killer (NK) cells play a crucial role in cytotoxicity, utilizing ligands like TRAIL and FasL, but are also susceptible to apoptosis via TRAIL receptors.
- Uterine NK cells interact with fetal trophoblasts, a critical interaction in pregnancy, where NK cell cytotoxicity towards trophoblasts is a key consideration.
Purpose of the Study:
- To investigate the expression of proapoptotic receptors and ligands on NK cells during interaction with trophoblast cells.
- To determine the impact of cytokines and chorionic villi factors on NK cell apoptosis receptor expression and function.
Main Methods:
- Utilized the NK-92 cell line as NK cells and the JEG-3 cell line as trophoblast target cells.
- Applied various cytokines (IL-1β, IL-15, IL-18, TNFα, IL-10, TGFβ) and conditioned media from chorionic villi explants as inducers.
- Assessed the expression of apoptotic receptors (DR4, DR5, DcR1) and ligands (TRAIL, FasL) on NK cells via flow cytometry.
Main Results:
- Cytokines TNFα and TGFβ modulated NK cell apoptotic receptor expression, increasing Fas and decreasing DR5, respectively.
- Soluble chorionic villi factors altered TRAIL and FasL expression, suggesting differential regulation of apoptosis mechanisms across trimesters.
- Trophoblast cells and chorionic villi factors reduced NK cell expression of TRAIL, DcR1, DR4, and DR5, indicating trophoblast-mediated inhibition of NK cell cytotoxicity.
Conclusions:
- Soluble factors from chorionic villi regulate NK cell resistance to apoptosis, likely by binding TRAIL and maintaining NK cell activity.
- Trophoblast cells appear to exert an inhibitory effect on NK cell cytotoxicity, modulating key apoptosis-related molecules.
- This study elucidates mechanisms by which NK cell activity is regulated in the context of trophoblast interaction, relevant to pregnancy immunology.
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