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

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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).