Cellular immune responses in pregnancy loss: T cell and NK cell
- Immune system regulation has important roles in dealing with semi-allogenic antigens during pregnancy. There are distinguished different roles in T cells in peripheral blood and endometrial T cells in pregnancy maintenance and loss.
T cell in peripheral blood
In peripheral blood, CD3+ T cell levels are not significantly different in women with a history of recurrent pregnancy loss compared to fertile women. However, during the first trimester of a pregnancy that ends in miscarriage, CD3+ T cell levels are notably lower than in women who successfully deliver a live infant. This decrease may be related to an increase in CD19+ B cells and/or CD56+ NK cells, which have been associated with pregnancy loss. About the potential role of Th1 and Th2 cytokines in pregnancy, the studies suggest that an elevated Th1:Th2 ratio may be linked to recurrent pregnancy loss.
Endometrial T cells:
Regarding endometrial T cells, it is mentioned that they may not play a significant role in implantation and pregnancy maintenance, as their numbers decrease considerably in the first trimester of gestation. However, differences in CD8+ and CD4+ cell numbers and CD4:CD8 ratios have been observed in recurrent aborters, suggesting altered endometrial immunological conditions in these cases.
There is also a role of natural killer (NK) cells in recurrent pregnancy loss, both in peripheral blood and endometrial bed biopsies. Activated NK cells, especially those in peripheral blood, have been associated with recurrent pregnancy loss, infertility, and assisted reproductive failures. They can recognize trophoblast cells and produce cytokines that may be abortogenic.
Additionally, NK cell activation markers like CD69+ and CD161+ have been linked to implantation failure.
Th2 Environment: Pregnancy is associated with a Th2 immune environment, characterized by an increase in CRTH2+ Th2 cells and CRTH2+ Tc2 (cytotoxic) cells at the maternal-fetal interface (implantation site) in the decidua. This suggests that Th2 and Tc2 cells may play a role in pregnancy maintenance, possibly recruited in response to PGD2 (prostaglandin D2) signaling.
Natural killer (NK) cells, specifically endometrial NK cells:
- Phenotypic Differences: Endometrial NK cells differ in phenotype (CD16-/CD56bright) from peripheral blood NK cells (CD16+/CD56dim). This distinction suggests potential functional differences between these cell populations during implantation and fetal development.
- Gene Expression: Gene expression analysis revealed significant differences between decidual NK cells and peripheral NK cells. Decidual NK cells express unique genes, including lectin-like receptors, killer cell Ig-like receptors, integrin subunits, and immunomodulatory proteins like galectin-1 and progestagen-associated protein 14, suggesting an immunoregulatory role for decidual NK cells during normal pregnancy.
- Role in Recurrent Pregnancy Loss: Studies have shown variations in the numbers and subsets of endometrial NK cells in cases of recurrent early pregnancy loss. Higher numbers of CD56+ NK cells and increased ratios of CD56bright : CD56dim cells have been associated with recurrent miscarriages, suggesting a potential role for NK subsets in these cases.
- Decidual NK Activity: Increased decidual NK cell activity and numbers have been observed in cases of anembryonic pregnancies and recurrent spontaneous abortion, indicating a potential link between heightened decidual NK cell activity and pregnancy losses.
- Cytokine Production: Decidual CD16-CD56bright NK cells isolated from early pregnancy produce various cytokines, including G-CSF, GM-CSF, M-CSF, TNF-alpha, IFN-gamma, LIF, and IL-8, which may play important roles in supporting a successful pregnancy. Additionally, the interaction of HLA-G molecules on trophoblast cells can stimulate vascular endothelial growth factor production by uterine NK cells, suggesting a role in promoting vascular development.
- Regulation by Cytokines: Decidual NK cell activity can be influenced by cytokines such as IL-2 and IL-4. IL-2 stimulation is induced by stem cell factor (SCF), which promotes NK cell proliferation. Conversely, IL-4 inhibits IL-2-induced NK cell activity and DNA synthesis in decidual NK cells, highlighting the intricate interplay of cytokines in regulating NK cell functions.
- Regulatory T Cells: The paragraph briefly mentions the importance of regulatory T cells (NKT cells) in pregnancy, with higher percentages of these cells observed in the decidual compared to peripheral blood. These cells appear to control the Th1/Th2 balance by producing IL-4 and IFN-γ at the maternal-fetal interface.