# The molecular mechanism of Aire

> **NIH NIH R01** · HARVARD MEDICAL SCHOOL · 2024 · $506,805

## Abstract

Autoimmune diseases are a growing health problem: there are many of them (>100); they are quite
frequent in toto (~10% of Americans); and their incidence has been increasing for decades. Autoimmunity results
from a breakdown in one or more central or peripheral mechanisms of lymphocyte tolerance induction or
maintenance. In the case of T cells, central tolerance is imposed within the thymus, key orchestrators being
medullary thymic epithelial cells (mTECs), which play critical roles in both negative selection of T effector cells
and positive selection of T regulatory cells (Tregs). A unique feature of mTECs is expression of hundreds of loci
encoding antigens typically associated with fully differentiated peripheral parenchymal cells (peripheral-tissue
antigens or PTAs). Most of this “misplaced” gene expression is driven by the transcriptional regulator Aire. Loss
of Aire in both mice and humans results in a multi-organ autoimmune disease; in addition, recent studies have
uncovered an association of Aire with several common human autoimmune diseases.
 During the last funding-cycle, we serendipitously discovered a second, previously unappreciated arm of
thymocyte tolerization: thymic mimetic cells. These cells are a heterogeneous set of (mostly) Aire-dependent,
post-Aire mTECs that have co-opted the lineage-defining transcription factors (LDTFs), chromatin-accessibility
landscapes, and gene-expression profiles of particular extra-thymic cell-types, while maintaining their mTEC
identity. To date, 15 different mimetic-cell subtypes have been identified, including tuft, muscle, ciliated, microfold
and sebocyte mTECs. Accrual of thymic mimetic cells depends critically on the LDTF(s) they express and
differentially on Aire. Directing expression of a neoantigen to mimetic cells tolerizes cognate thymocytes.
 Building on this discovery, and abiding by the molecular focus of this grant, THE OVERALL GOAL OF
THIS PROPOSED PROJECT IS TO ELUCIDATE THE MOLECULAR MECHANISMS UNDERLYING MIMETIC
mTEC GENERATION, IN PARTICULAR MOLECULAR RELATIONSHIPS BETWEEN THE AIRE-BASED
AND MIMETIC-CELL BASED PATHWAYS OF T-CELL TOLERANCE INDUCTION. This goal will be addressed
by three independent and cross-informing Aims:
A. To determine how Aire and LDTFs influence each other’s genomic activities.
B. To determine how modulating the binding of Aire to chromatin in Aire-stage mTECs influences the
accrual of mimetic-cell subtypes at the post-Aire stage.
C. To unravel the lineage relationships of thymic mimetic cells.
 This study will yield novel (potentially the first) information on how thymic mimetic cells are generated –
in particular how the Aire-based and mimetic-cell-based arms of thymocyte tolerance induction are integrated.
This information should prove highly valuable in both dissecting mechanisms of diverse autoimmune diseases
and, potentially, manipulating thymic cells or molecules to treat or avoid them.

## Key facts

- **NIH application ID:** 10801171
- **Project number:** 2R01AI088204-11
- **Recipient organization:** HARVARD MEDICAL SCHOOL
- **Principal Investigator:** DIANE J MATHIS
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $506,805
- **Award type:** 2
- **Project period:** 2010-12-10 → 2028-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10801171

## Citation

> US National Institutes of Health, RePORTER application 10801171, The molecular mechanism of Aire (2R01AI088204-11). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10801171. Licensed CC0.

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