# The role of paracrine mTOR signaling in regulating thymus size and function

> **NIH NIH R21** · UNIVERSITY OF TEXAS HLTH SCIENCE CENTER · 2021 · $231,625

## Abstract

Summary
T lymphocytes are critical mediators of the adaptive immune response, however, they are continuously lost
throughout the lifespan, and therefore must be continuously replaced. The thymus is the primary site of new T
cell generation, and the unique thymic stromal microenvironment directs T cell differentiation, self-tolerance and
self-restriction. However, the size of the thymus declines precipitously beginning relatively early in life, resulting
in declining production of new, naïve T cells. As a result, homeostatic mechanisms driven expansion of memory
cells in the periphery, driving a shift toward an oligoclonal T cell memory, leaving the elderly less responsive to
vaccines and new infections, especially viral infections such as flu. Preventing or reversing age-associated
thymic atrophy therefore hold great potential for extending the healthspan in the aging population. The
mechanisms governing thymic atrophy have been difficult to identify, because the primary targets of atrophy,
cortical thymic stromal cells, are rare and difficult to isolate. To understand these mechanisms, we have applied
an informatic approach to characterize the transcriptional response of thymic stromal cells during age-related
atrophy or experimentally induced regeneration. In a recently published study, we showed that cortical thymic
epithelial cells (cTECs) display a unique morphology characterized by extensive looping projections, while
atrophy is associated with by contraction of these projections, which are renewed during induced regeneration.
In addition, we used a combination of genetic reporter models and biosynthetic labeling to show that cTEC
numbers do not decrease during atrophy of increase during regeneration. Instead, these dynamic processes
appear to be regulated by changes in cTEC size and branching morphology. Further informatic analysis indicated
that paracrine signaling between medullary and cortical TEC, particularly involving the mammalian target of
rapamycin (mTOR) pathway, was likely to play a key role in the mechanisms of atrophy and regeneration. We
will test the hypothesis that paracrine mTOR signaling maintains thymus size using tissue-specific transgenic
mice overexpressing mTOR activating ligands in medullary thymic epithelial cells (mTEC).

## Key facts

- **NIH application ID:** 10218405
- **Project number:** 1R21AI154109-01A1
- **Recipient organization:** UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
- **Principal Investigator:** Ann Venables Griffith
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $231,625
- **Award type:** 1
- **Project period:** 2021-02-16 → 2023-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10218405

## Citation

> US National Institutes of Health, RePORTER application 10218405, The role of paracrine mTOR signaling in regulating thymus size and function (1R21AI154109-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10218405. Licensed CC0.

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