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Immune Checkpoint Molecules and Maternal–Fetal Immunity

  • REVIEW
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Abstract

Purpose of Review

Because the fetus expresses paternally-derived foreign antigens, pregnancy poses unique immune challenges. The maternal immune system must balance protecting the semi-allogeneic fetus from immune rejection with defending the mother and fetus from pathogens. Fetally-derived trophoblast cells of the placenta serve as the immunologic interface with soluble and cellular maternal immune effectors and are thereby essential partners in supporting these tightly regulated interactions. While there are multiple ways that the maternal–fetal immune interface is controlled in a healthy pregnancy, this review highlights several of the immune checkpoint regulators thought to be centrally involved in maternal–fetal immunoregulation.

Recent Findings

Reproductive immunologists have shown that those fetal trophoblast cells that directly encounter maternal immune cells share many common features with cancer cells, shifting the paradigm of placental immunology away from transplantation biology and toward our extensive understanding of tumorigenesis. Both the post-implantation placenta and the growing neoplasm have many shared goals, including invasion, robust cellular proliferation, angiogenesis, and modulation of host immunity. One way in which both the human placenta and cancer cells protect themselves from immune attack is through the loss of, or neoexpression of, several important cell surface regulators of specific immune interactions known as immune checkpoints. Here, we will discuss several ways that tumors and the placenta utilize immune checkpoint pathways and inhibitors, including the loss of most classical major histocompatibility complex (MHC) molecules and neoexpression of several nonclassical MHC molecules, expression of novel immunosuppressive B7 family members and cell adhesion molecules, such as CD47, and modulation of indoleamine 2,3-dioxygenase (IDO) enzyme activity.

Summary

Finely tuned immune adaptation is fundamental to a successful reproduction. Failure to implement such adaptations can result in a variety of disorders, including pregnancy loss, abnormal placental invasion (e.g., placenta accreta/percreta), preeclampsia, and intrauterine growth restriction. Improved understanding of complex maternal-fetal immune interactions will be crucial to discover mechanisms underpinning these pregnancy complications, which, in turn, will help inform preventative and/or therapeutic clinical interventions.

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Funding

The authors’ research is supported by grants 1RO1HD094937 from the National Institutes of Health (DJS), R21A1145071 from the National Institutes of Health (DJS, JZ), and pilot grant from the University of Missouri (SC).

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Authors and Affiliations

  1. Duke Obstetrics & Gynecology, Duke University School of Medicine, Durham, NC, 27710, USA

    Sloane Mebane, Jie Zhou & Danny J. Schust

  2. Department of Obstetrics, Gynecology, and Women’s Health, University of Missouri School of Medicine, Columbia, MO, 65212, USA

    Sehee Choi

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  1. Sloane Mebane
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  2. Jie Zhou
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  3. Sehee Choi
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  4. Danny J. Schust
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S.M., J.Z., and S.C. wrote the main manuscript text. All authors reviewed the manuscript.

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Correspondence to Danny J. Schust.

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Mebane, S., Zhou, J., Choi, S. et al. Immune Checkpoint Molecules and Maternal–Fetal Immunity. Curr Obstet Gynecol Rep 13, 37–45 (2024). https://doi.org/10.1007/s13669-024-00372-3

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