Equine pregnancy-specific glycoprotein CEACAM49 secreted by endometrial cup cells activates TGFB.

This research explores how equine pregnancy-specific glycoprotein CEACAM49 helps activate TGFB in the womb to foster immune tolerance during pregnancy. It finds that the special protein binds to latency-associated peptides in TGFB to activate it and maintain immune tolerance.

Equine Pregnancy and Immune Response

• The study begins by setting the context of early equine pregnancy and the events that occur to ensure the immune system does not attack the developing fetus. It mentions that a type of cell called the chorionic girdle cells invade the endometrium to form endometrial cups (ECs), which are known to express MHC molecules.
• These MHC molecules prompt an immune response, which sees a significant accumulation of maternal CD4+ and CD8+ T cells around the EC. However, despite this immune response, the ECs are not destroyed, thanks to immune tolerance.
• Though it is known that the EC environment is rich in TGFB and FOXP3+, CD4+ T cells, the specific mechanisms that result in this tolerance have not been fully understood.

Role of Pregnancy-Specific Glycoproteins

• The researchers previously discovered that equine trophoblast cells produce pregnancy-specific glycoproteins (PSGs). Given that human and murine PSGs are known to activate latent TGFB, the team hypothesized that equine PSGs could have a similar activity.
• The researchers then experimented with PSG CEACAM49 and TGFB1 and TGFB2. They discovered that CEACAM49 can directly bind to latency-associated peptides of both types of TGFB.
• The binding of CEACAM49 essentially wakes up or ‘activates’ latent TGFB1, which was proven using ELISA and cell-based assays.
• Importantly, the activation of TGFB appears to be a unique function of PSGs within the human CEA family, because other CEA proteins (CEACAM1, 3, 5, 6, 8) do not activate this cytokine. This finding further confirms the classification of CEACAM49 as an equine PSG.

Hypothesis and Future Studies

• Based on these results, the researchers hypothesize that the activation of latent TGFB in the EC environment by equine PSGs produced by invading trophoblast cells, could contribute to generating regulatory T cells (Tregs) to sustain immune tolerance.
• This research contributes valuable insights into equine pregnancy, paving the way for future studies to unravel the myriad mechanisms that underpin immune tolerance during pregnancy.