# Decidual NK response to infection

> **NIH NIH R01** · BOSTON CHILDREN'S HOSPITAL · 2021 · $835,797

## Abstract

Decidual NK cells (dNK), the largest population of maternal immune cells at the maternal-fetal interface in the
first trimester of pregnancy, directly contact fetal extravillous trophoblasts (EVT), which invade the decidua to
remodel the vasculature to establish the blood supply to the placenta. The direct contact between dNK and EVT
challenges the maternal immune system, which must tolerate fetal cells, but still protect against infection. How
dNK protect the placenta and fetus from infection is not well understood. Most clinically significant infections of
the placenta and fetus are caused by intracellular pathogens (bacteria, parasites and viruses), for which killer
lymphocytes (NK and cytotoxic T lymphocytes) are key to systemic protective immunity. In the first trimester,
when infection has the most serious fetal consequences, there are few T cells in the decidua. Although dNK
have cytotoxic granules, express all the cytotoxic molecules, and kill conventional NK cell targets, their cytolytic
activity is reduced compared to peripheral blood NK cells. Moreover, although dNK form contacts with EVT, they
do not degranulate or kill
human cytomegalovirus-infected EVT. These findings emphasize the difficulties of
maternal immune cells to clear placental infections and prevent transmission of pathogens to the unborn child.
This proposal investigates a novel and exciting mechanism we recently discovered by which dNK kill L.
monocytogenes (Lm) inside trophoblasts, without killing the host cell. dNK express large amounts of granulysin
(GNLY), an antimicrobial peptide found both in cytotoxic granules and the cytosol that preferentially disrupts
microbial, relative to mammalian, membranes. Our preliminary data suggest that dNK establish nanotube
cytoplasmic connections to EVT. Without forming a conventional immune synapse or degranulating, dNK
transfer GNLY via nanotubes to EVT, but not other cytotoxic molecules (perforin, granzymes), which would kill
the host cell. This mechanism provides an elegant solution to the immune dilemma of pregnancy – defense
against infection while maintaining tolerance of the fetus and placenta. As far as we are aware, this is the first
evidence for an immune function of nanotubes. Nanotube transfer of GNLY and potentially other bioactive
molecules from dNK to EVT helps control intracellular infection and could regulate trophoblast functions. Our
goals are to confirm our preliminary data showing that intracellular microbes, but not fetal cells, are killed by
dNK transfer of GNLY, independently of perforin and granzymes; identify which infected maternal and fetal cells
in the placenta dNK protect and by what mechanism; explore the mechanism responsible for nanotube
formation, which molecules are transferred and which pathogens important in pregnancy are susceptible. The
protective role of GNLY and dNK will also be evaluated in human placental tissue explants and in mice by
comparing pregnancy outcomes following infection of G...

## Key facts

- **NIH application ID:** 10160812
- **Project number:** 5R01AI145862-03
- **Recipient organization:** BOSTON CHILDREN'S HOSPITAL
- **Principal Investigator:** Judy Lieberman
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $835,797
- **Award type:** 5
- **Project period:** 2019-06-19 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10160812

## Citation

> US National Institutes of Health, RePORTER application 10160812, Decidual NK response to infection (5R01AI145862-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10160812. Licensed CC0.

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