# HLA-F in maternal-fetal immune crosstalks

> **NIH NIH R21** · UNIVERSITY OF ILLINOIS AT CHICAGO · 2023 · $239,850

## Abstract

ABSTRACT
 Pregnancy is a complex state that involves immune crosstalks between maternal cells in the decidua and
fetal cells. This communication plays an important role in protecting the fetus from rejection. Extravillous
trophoblasts (EVTs) are critical fetal cells that shape the immunological microenvironment at the maternal-fetal
(M-F) interface. EVTs express a unique set of major histocompatibility complex (MHC I) molecules on their
surfaces: the classical HLA-C and non-classical HLA-E, -F, and -G molecules. Quite exceptionally, EVTs do
not express HLA-A and HLA-B. HLA-C, -E, and -G molecules have been associated with mechanisms of
immune tolerance at the M-F interface, and whether HLA-F functions similarly is less well understood. HLA-F is
unique among MHC I molecules in several ways: 1. HLA-F exists in more than one molecular form, with and
without associated peptides and b2m; 2. HLA-F binds peptides that are unconventionally long, ranging from
8mers to more than 20mers; and 3. Inhibitory and activating receptors on natural killer (NK) cells can
distinguish between peptide-filled and peptide-deficient HLA-F molecules. It is therefore logical to propose that
a role for HLA-F in M-F immune crosstalks involves interactions between HLA-F expressed on EVTs and NK
receptors on decidual NK cells. This is reinforced by the knowledge that HLA-F expression on EVTs is most
abundant in early pregnancy, and that NK cells constitute the largest population of maternal immune cells in
the decidua during the first trimester of pregnancy. Thus, to develop an understanding of how HLA-F functions
as an immunoregulatory molecule, it is critical that we have a strong understanding of the peptide binding
properties of HLA-F and the mechanisms by which peptides modulate interactions with NK cell receptors. This
R21 application is an early-stage investigation that aims to fill unresolved gaps in our knowledge of HLA-F
immunobiology. In two aims, we propose to examine the unique landscape of HLA-F peptides in relation to
specialized aminopeptidases that normally generate MHC I immunopeptidomes inside cells, as well as address
key questions centered on why HLA-F presents peptides of extraordinarily long lengths, what biochemical and
structural properties of HLA-F support binding of long peptides, and what is the role of peptides in modulating
HLA-F interaction with NK cells. For this, we will use a combination of cell-based, biochemical, and structural
approaches. Upon completion of this project, we will have generated new knowledge on HLA-F that will help
understand how its expression on EVTs and engagement with receptors on decidual NK cells, can support a
critical regulatory role in immune crosstalks during the early stages of pregnancy. Given that pregnancy
complications are often associated with a loss of immune tolerance mechanisms, a characterization of HLA-F
as proposed here is important for stimulating new ideas in managing and decreasing the risks associate...

## Key facts

- **NIH application ID:** 10667879
- **Project number:** 1R21AI183287-01A1
- **Recipient organization:** UNIVERSITY OF ILLINOIS AT CHICAGO
- **Principal Investigator:** MARLENE BOUVIER
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $239,850
- **Award type:** 1
- **Project period:** 2023-09-22 → 2025-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10667879

## Citation

> US National Institutes of Health, RePORTER application 10667879, HLA-F in maternal-fetal immune crosstalks (1R21AI183287-01A1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10667879. Licensed CC0.

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