# Defining the Role of Aire in eTACs and its Contribution to Peripheral Immune Tolerance

> **NIH NIH F31** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2024 · $16,164

## Abstract

PROJECT SUMMARY/ABSTRACT
The autoimmune regulator (Aire) gene, a key transcriptional regulator expressed in medullary thymic epithelial
cells (mTECs), has been shown to be crucial for central tolerance by inducing tissue specific antigen (TSA)
expression in mTECs. Interestingly, Aire is also found in extrathymic Aire-expressing cells (eTACs) in the
secondary lymphoid organs such as the spleen and lymph nodes. We previously found that eTACs are
hematopoietic antigen-presenting cells (APCs) and consist of two similar cell types: CCR7+ Aire-expressing
migratory dendritic cells (AmDCs) and an Aire-high population co-expressing Aire and retinoic acid receptor–
related orphan receptor γt (ROR γt) that we termed Janus cells (JCs). Functionally, eTACs are capable of
enforcing deletion and anergy on self-reactive T cells, and self-antigen expression in eTACs is sufficient to
prevent autoimmunity. The transcriptional, genomic, and functional symmetry between eTACs (both JCs and
AmDCs) and mTECs potentially identifies a core program driven by Aire that may influence self-representation
and tolerance across the spectrum of immune development. However, the lineage relationship of eTACs, what
role Aire plays in these populations, and how extrathymic Aire and eTAC subsets contribute to immune
homeostasis are still unknown. This proposal will test the hypothesis that Aire is inducing a tolerogenic
phenotype in eTACs and that extrathymic Aire and eTACs are important for enforcing peripheral immune
tolerance. Aim 1 of this proposal will define the lineage relationship between eTACs subsets, their antigen
processing and presentation functions, and their migratory abilities. Aim 2 will define the cell-intrinsic functions
of Aire in eTACs at both the transcriptional and chromatin level. Aim 3 will investigate the contribution of
extrathymic Aire and eTACs in maintaining normal immune homeostasis. This proposal will be carried out using
a variety of methods including single cell multiomics, flow cytometry, and functional approaches such as ex vivo
co-cultures and in vivo monitoring of autoimmunity utilizing novel genetic mouse models. By characterizing
eTAC subsets and investigating the functional roles of extrathymic Aire and eTACs, this work will help
further elucidate the function of Aire and define basic peripheral tolerance mechanisms. Furthermore,
understanding the biology of these tolerogenic populations may have significance for a range of clinical
applications from autoimmunity to tumor immunity to maternal-fetal tolerance. This research project and
fellowship training will be conducted at a top-funded research institution, the University of California,
San Francisco (UCSF), in the laboratories of Dr. James Gardner and Dr. Mark Anderson. Dr. Gardner has
expertise in studying peripheral Aire/eTACs and the generation of genetic mouse models. Dr. Anderson is a
world expert on Aire biology, thymic selection, and immune tolerance, and a highly respected mentor and...

## Key facts

- **NIH application ID:** 10871694
- **Project number:** 5F31AI172348-03
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** Jiaxi Wang
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $16,164
- **Award type:** 5
- **Project period:** 2022-07-01 → 2024-09-11

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10871694

## Citation

> US National Institutes of Health, RePORTER application 10871694, Defining the Role of Aire in eTACs and its Contribution to Peripheral Immune Tolerance (5F31AI172348-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10871694. Licensed CC0.

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