# Autoimmune Regulator gene (Aire)-mediated tolerance to pregnancy-associated self-antigens

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2020 · $790,304

## Abstract

PROJECT SUMMARY
The question of how the fetus and placenta avoid rejection by the maternal immune system has puzzled
generations of immunologists and reproductive biologists. A great deal of work on this immunological paradox
has focused on the problem of how the maternal immune system tolerates fetal alloantigens. However, another
problem during pregnancy entails the exposure of the mother to numerous newly-induced or strongly
upregulated self-antigens encoded by the mother’s own genome. Many of these “pregnancy associated
antigens” (PAAs) have not been produced since the mother herself was a fetus with a placenta and are only
encountered in postnatal life when she becomes pregnant. A crucial component in imposing tolerance to self-
antigens is the autoimmune regulator gene (Aire), which promotes the expression of tissue-restricted antigens
in medullary thymic epithelial cells (mTECs) and extrathymic cells Aire expressing cells (eTACs), leading to
clonal deletion or Treg conversion of self-reactive T cells. The role of Aire in supporting healthy pregnancy has
not yet been explored. Surprisingly, we found that selective depletion of maternal Aire-expressing cells in mice
during early in pregnancy results in a dramatic phenotype of pregnancy loss (both failure to become pregnant
after plugging and early embryo resorption), along with a significant increase in the conventional T cell to Treg
cell ratio in the thymus and an influx of maternal T cells into the resorbing uterus. These data are consistent
with other hints in the literature such as the presence of anti-placental antibodies and pregnancy complications
(such as fetoplacental insufficiency) in patients with Aire deficiency. Based on these data, we hypothesize that
Aire-mediated expression of PAAs in mTECs and eTACs supports healthy pregnancy by promoting deletion of
PAA-reactive T cells and induction of PAA-specific Tregs. By extension, immune responses to these antigens
in the absence of Aire may play a role in pregnancy complications. This hypothesis shifts the current paradigm
regarding maternal-fetal tolerance from focusing on the potential threat of alloantigens to the unknown potential
value of imposing tolerance to a unique set of PAAs encoded by the maternal genome. In this proposal, we will
first assess the temporal role of Aire during early vs late pregnancy and the relative contributions of mTECs vs
eTACs in supporting healthy pregnancy (Aim 1). We will use a combination of unbiased biochemical and
transcriptomic analyses to identify putative Aire-regulated PAAs and validate their expression in mice and in
patients with infertility (Aim 2). Lastly, we will investigate the function of Aire in generating PAA-specific Tregs
using a novel transgenic mouse to express a model antigen under the control of Aire in maternal mTECs and
eTACs (Aim 3). Our short-term goal is to understand the mechanisms by which Aire supports healthy
pregnancy. Our long-term goal is to identify specific PAAs...

## Key facts

- **NIH application ID:** 10000016
- **Project number:** 5R01AI145858-02
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** Tippi Mackenzie
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $790,304
- **Award type:** 5
- **Project period:** 2019-08-21 → 2024-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10000016

## Citation

> US National Institutes of Health, RePORTER application 10000016, Autoimmune Regulator gene (Aire)-mediated tolerance to pregnancy-associated self-antigens (5R01AI145858-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10000016. Licensed CC0.

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