Leukemia inhibitory factor shifts immune checkpoint gene expression in abortion-prone mice

The work, led by Yeganeh Lalehzari, Fateme Zare, Hossein Ansariniya and Hossein Hadinedoushan, examined ten checkpoint-related genes in an abortion-prone mouse model and found that a single injection of the factor altered the expression pattern of several of them.

The researchers used the well-established mating combination of female CBA/J mice with male DBA/2J mice, which produces an abortion-prone phenotype, alongside female CBA/J mice mated with male BALB/c mice as a comparison. On day four after the formation of a vaginal plaque, they measured the expression of PD-1, PD-L1, TIM-3, Gal-9, LAG-3, Gal-3, ST6GALNAC1, LAIR1, GITR and VISTA in the decidual tissue.

On that fourth day of pregnancy, the abortion-prone mice showed a distinctive pattern: expression of PD-1 and VISTA was lower than in the comparison group, while expression of TIM-3, LAG-3, LAIR-1 and GITR was higher.

To test whether leukemia inhibitory factor could influence this pattern, the team injected 40 micrograms of the factor intraperitoneally on day three of pregnancy into abortion-prone females, with phosphate-buffered saline injections serving as the control in the other groups. The treated animals were assessed on day fourteen of pregnancy, while the control group was assessed on day seven. According to the results, the factor upregulated the expression of PD-1 and Gal-9 genes, and on the seventh day of pregnancy the expression of TIM-3, Gal-3, VISTA, LAIR-1 and GITR genes increased, with changes also observed on the fourteenth day.

The authors conclude that, based on their findings, the factor may modulate immune checkpoint-related gene expression in the abortion-prone mouse model.

The researchers are careful to frame the study as an early step rather than a therapeutic demonstration. The experiment measured gene expression, not protein levels, and it did not test whether the observed transcriptional changes translated into fewer pregnancy losses or improved outcomes for the animals. The authors explicitly state that further studies examining protein expression, immune cell-specific responses and functional mechanisms are needed before any translational applications can be considered.

That caution matters because the leap from messenger RNA levels in whole decidual tissue to functioning immune regulation in a living pregnancy is a wide one. Gene expression in a tissue homogenate cannot reveal which cell populations are responsible for the changes, whether the altered checkpoint signals are active at the protein level, or how the shifts interact with the many other immune pathways operating at the maternal-fetal interface. The study also relies on a single dose and timing of the factor, and the control and treated groups were assessed at different days of pregnancy, which the authors describe in their methods.

Mapping how these checkpoint-related genes behave in an abortion-prone strain, and how leukemia inhibitory factor altered their expression in this model, gives other researchers a defined set of targets for follow-up work at the protein and cellular level.

For now, the findings stand as a mouse-model observation: leukemia inhibitory factor, delivered as a single injection before the abortion-prone window, altered the expression of several immune checkpoint-related genes in decidual tissue. Whether those transcriptional shifts can be developed into a deeper understanding of recurrent pregnancy loss, or eventually into clinical approaches, depends on the protein-level, cell-specific and mechanistic studies the authors themselves call for as the necessary next stage.

Subject of Research: The effect of leukemia inhibitory factor on immune checkpoint-related gene expression in an abortion-prone mouse model of recurrent pregnancy loss

Article Title: Effect of leukemia inhibitory factor on immune checkpoint-related gene expression: a possible new window to overcome recurrent pregnancy loss and boost immune system tolerance

Article References: Lalehzari, Y., Zare, F., Ansariniya, H., & Hadinedoushan, H. (2026). Effect of leukemia inhibitory factor on immune checkpoint-related gene expression: a possible new window to overcome recurrent pregnancy loss and boost immune system tolerance. BMC Immunology. https://doi.org/10.1186/s12865-026-00920-x

Image Credits: AI Generated

DOI: 10.1186/s12865-026-00920-x

Keywords: recurrent pregnancy loss, leukemia inhibitory factor, immune checkpoints, decidua, PD-1, TIM-3, Gal-9, LAG-3, VISTA, mouse model, reproductive immunology, immune tolerance