What Makes the Placenta So Tough? Placental Factors in Immunomodulation
By: Hadeel Saab and Mari Yamamoto
Immune checkpoint molecules (such as CTLA-4, TIM-3 and PD-1) work to prevent autoimmunity and defend against infections. During pregnancy, the maternal immune system faces the challenge of a semi-allogeneic fetus, as well as the risk of infection, and these immune checkpoint molecules have been shown to have important roles.
- CTL-4 caused increases of Treg cells and Th2 as well as decreased Th1 cytokine production, suggesting an impressive immunosuppressive effect.
- With its ligand galectin-9, TIM-3 and the pathway seem to participate in the activation and inhibition of the immune response by leading to the apoptosis of Th1 and Th17 cells and thus inducing immunotolerance.
- Once it binds to its ligands, PD-1 generates a strong inhibitory effect that down-regulates pro-inflammatory T cell activity.
- The co-expression of TIM-3 and PD-1 may have a protective, anti-inflammatory effect.
Click here to read a full review of the roles of these immune checkpoint molecules in both healthy pregnancies and pregnancies with complications.
What Are Galectins?
Galectins are proteins that act as immunomodulators, and in pregnancy, they regulate the maternal immune response. Galectin-13 and galectin-14 are only expressed by the placenta, and play an important part in the regulation of the maternal immune balance. A paper by researchers in Hungary looked at their effects on T cell functions in healthy pregnancies and miscarriages:
- Expression of galectins -13 and -14 are reduced at the maternal-fetal interface in fetal rejection or miscarriages, leading to the conclusion that this lower expression may be contributing to an immune balance that interferes with pregnancy.
- Gal-13 and gal-14 also induced apoptosis in T cell populations by increasing the expression of activation marker CD95.
- These galectins may also play a role in angiogenesis, as they induced the production of IL-8 in T cells, a cytokine that exerts a pro-angiogenic effect on endothelial cells.
Immunomodulation via L-Tryptophan
L-Tryptophan (TRP) may be most famously known as the precursor amino acid to the neurotransmitter serotonin, but this is not the only pathway by which it carries out important functions. Of TRP’s many pathways of metabolism, two have been shown to be involved in fetal development: the serotonin pathway and the kynurenine pathway.
The serotonin pathway involves the use of the mother’s TRP to synthesize serotonin (5-HT) and melatonin in the placenta. The 5-HT is released into fetal circulation to aid with fetal brain development, while the melatonin is released to help regulate the fetus’ circadian rhythmicity.
The Kynurenine pathway (Kyn) also occurs in the placenta and is primarily involved in preventing maternal rejection of the fetus by the immunomodulatory properties of the Kyn metabolites. More specifically, the enzyme IDO breaks down TRP to produce the Kyn metabolites, 3-HK, 3-HAA and quinolinic acid, which act as immunosuppressants of allogeneic T-cell proliferation (type 1 T helper cells). Thus, maternal T cell attack of the fetus is avoided by the production of these Kyn metabolites.
These placental factors help to combat the challenges that the maternal immune system faces during pregnancy. Their immunomodulatory effects are important in maintaining a healthy pregnancy, and it’s these effects that give them the potential to aid in the development of treatments for autoimmune diseases like T1D. Immunosuppression and angiogenesis are crucial focuses of T1D research, and understanding how these factors function in the placenta may provide critical insight.