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. 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. We found that paracrine signaling between medullary and cortical epithelial cells (TECs), particularly involving the mammalian target of rapamycin (mTOR) pathway, was likely to play a key role in the mechanisms of atrophy and regeneration. To develop tools required test the hypothesis mTEC-derived signals (particularly FGF21) promote thymus growth, and to facilitate more extensive mechanistic studies of paracrine regulation of thymus function, we recently identified a gene (LPO) that drives specific expression of mCherry in most mTEC within the thymus. Here, we propose the generation of similar knock-in mice in which LPO drives expression of Cre recombinase, allowing tissue-specific genetic manipulation of mTECs. We will also use the newly generated model to investigate the role of mTEC-derived FGF21 using FGF21LoxP mice.

Narrative The thymus atrophies precipitously beginning relatively early in life, resulting in declining production of new, naïve T cells, driving a shift toward an oligoclonal T cell memory, leaving the elderly less responsive to vaccines and new infections, especially viral infections. We recently showed that paracrine signaling between medullary and cortical thymic epithelial cells (TEC) involving the mammalian target of rapamycin pathway, is a key regulator of thymus growth. In this study we will generate new mTEC tissue-specific mouse models to test the hypothesis that paracrine fibroblast growth factor 21 (FGF21) signals are required for thymus growth and maintenance during aging.