# Role of the microenvironment in regulating early stages of thymic involution and central tolerance

> **NIH NIH P01** · UNIVERSITY OF ARIZONA · 2024 · $757,731

## Abstract

ABSTRACT-Project 2
 During the process of age-associated thymus involution, T cell output progressively declines, contributing to
a reduction in naive T cells in older humans and mice. The resultant decline in new T-cell responses to
pathogens, vaccines, and cancers, leads to compromised immunity and increased morbidity with age. Thus, it
is important to elucidate mechanisms underlying reduced thymic function in order to improve human health
throughout the lifespan. In the past Project period, we found that early T-cell progenitors (ETPs), which give rise
to all downstream thymocyte subsets, decline in numbers surprisingly early, by 3 months (mo) of age. ETP
cellularity remains proportional to downstream thymocyte subsets at all ages, indicating the early decline in ETPs
sets the stage for diminished thymopoiesis during thymic involution. Because ETPs are the direct progeny of
circulating thymic seeding progenitors (TSPs), we anticipated a decline in the number of functional TSP niches
by 3mo of age. However, our data reveal that the available TSP niches do not decline through at least 12mo of
age, raising the question of what mechanisms underlie the early reduction in ETPs. Our preliminary data suggest
that changes in the BM and thymus microenvironments contribute to the early loss in ETPs. Although the
underlying mechanisms are not yet resolved, preliminary data suggest diminished NOTCH signaling in BM
lymphoid progenitors and thymic ETPs contribute. Thus, we will use genetic mouse models and advanced
imaging approaches to test if reduced expression of Notch ligands, and/or changes in other signals identified
through additional single-cell transcriptional profiling (Core B), are responsible for the early decline in lymphoid
progenitors in the BM (Aim 1) and ETPs in the thymus (Aim 2), and whether comparable mechanisms impact
the aging human thymus (Core C). We will also test if restoring NOTCH signaling rescues cellularity of BM
lymphoid progenitors, ETPs and thymocytes, and downstream T cell function in aging mice (P3 and Core D).
 Changes in the cellular composition and organization of the thymic microenvironment during involution
may impact not only the quantity, but also the quality of developing T cells with age. During the previous Project
period, we found that by middle age, the thymus becomes impaired in its ability to support central tolerance
through both negative selection and regulatory T cell generation, particularly in response to low avidity self-
antigens. New onset autoimmunity also peaks at middle age in humans, suggesting a role for impaired central
tolerance. Thus, we will analyze current single-cell transcriptional profiling datasets from P2 and P1 (Core B)
and perform live 2-photon imaging and thymic slice assays to identify age-associated changes in the mouse and
human (Core C) thymic microenvironments that impair central tolerance and increase autoimmune susceptibility
by middle-age (Aim 3). P2 is tightly integrated with...

## Key facts

- **NIH application ID:** 10851685
- **Project number:** 5P01AG052359-07
- **Recipient organization:** UNIVERSITY OF ARIZONA
- **Principal Investigator:** Lauren Ilyse Richie EHRLICH
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $757,731
- **Award type:** 5
- **Project period:** 2017-09-15 → 2028-02-29

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10851685

## Citation

> US National Institutes of Health, RePORTER application 10851685, Role of the microenvironment in regulating early stages of thymic involution and central tolerance (5P01AG052359-07). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10851685. Licensed CC0.

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