# Regulation of HLA-C in Human Trophoblasts and its Impact on Preterm Birth

> **NIH NIH R21** · HARVARD UNIVERSITY · 2020 · $211,250

## Abstract

ABSTRACT
Spontaneous preterm birth (SPTB) is a major public health problem world-wide, accounting in the United States
for about 10% of all live births (380,000 cases per year) with an estimated cost of nearly $30 billion per year.
This proposal is focused on HLA-C, the only highly polymorphic alloantigen expressed by invading extravillous
trophoblasts (EVT) at the maternal-fetal interface. HLA-C expression on EVT has a dual role as the major
molecule to which maternal-fetal tolerance must be generated but also as the principal molecule involved in
immune defense against viruses and bacteria in the placenta. EVT that form the fetal side of the maternal-fetal
interface express a triad of HLA molecules, HLA-C, HLA-G, and HLA-E that play critical roles in maternal-fetal
tolerance (but do not express the classical polymorphic HLA-A and HLA-B proteins). HLA-E that is expressed at
a low level functions as an inhibitor of NK cells that express its ligand CD94/NKG2A. HLA-G is directly involved
in the generation of tolerance to the killer cells (NK cells and CD8+ T cells) in the maternal decidua. HLA-E and
HLA-G exhibit only minimal polymorphism, whereas HLA-C is highly polymorphic with over 3500 alleles thus far
identified. HLA-C is therefore the principal molecule to which immune tolerance must be generated to prevent
allogeneic rejection of the fetus. As the only polymorphic HLA molecule present at this site, it is also the main
molecule able to presents peptides from pathogens to T cells. Thus HLA-C is essential for clearance of placental
infections as well as in preventing pathogens from crossing the maternal-fetal interface and infecting the fetus.
High HLA-C cell surface expression levels were shown to be important in the control of peripheral infections as
well as development of inflammatory disease. For example, high cell surface levels of HLA-C are i) found on
peripheral lymphocytes in HIV non-progressors, HIV-positive individuals who do not progress to AIDS, ii)
associated with increased inflammatory responses in Crohn's disease and iii) increased the generation of
cytotoxic T lymphocytes to HLA-C mismatches in hematopoietic transplant patients. These data suggest a broad
influence of HLA-C expression levels in inflammation and human disease that has thus far not been investigated
in the development of severe pregnancy complications. Generating high levels of HLA-C at the maternal-fetal
interface may be a route to control of viruses such as human cytomegalovirus (HCMV), and diminish congenital
defects associated with HCMV infection. On the other hand high HLA-C levels may increase immune recognition
and generation of detrimental T cell responses that contribute to sterile inflammatory responses in the placenta
and fetal membranes. Two-thirds of SPTB are associated with infection, while the other third is related to sterile
inflammation. Understanding the generation and the role of HLA-C expression on EVT will therefore contribute
to our underst...

## Key facts

- **NIH application ID:** 9822167
- **Project number:** 5R21AI138019-02
- **Recipient organization:** HARVARD UNIVERSITY
- **Principal Investigator:** JACK L STROMINGER
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $211,250
- **Award type:** 5
- **Project period:** 2018-11-14 → 2021-10-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9822167

## Citation

> US National Institutes of Health, RePORTER application 9822167, Regulation of HLA-C in Human Trophoblasts and its Impact on Preterm Birth (5R21AI138019-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9822167. Licensed CC0.

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