Role of paracrine mTOR signaling in regulating thymus size and function.

Abstract

Abstract The thymus is the primary site of 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 relatively early in life, resulting in declining production of naïve T cells. Homeostatic mechanisms drive 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 holds potential for extending the healthspan. 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. Using an informatic approach to characterize the transcriptional response of thymic stromal cells during age-related atrophy or experimental regeneration, we previously showed that cortical thymic epithelial cells (cTECs) display a unique morphology characterized by extensive looping projections. Atrophy is associated with contraction of these projections, which are renewed during induced regeneration. Further informatic analysis suggested that paracrine mTOR signaling in cTECs promoted by ligands expressed in medullary TECs (mTECs) may be required to maintain the cellular architecture of the cortical stroma and preserve thymus size. To test these hypotheses, we generated two new tissue-specific transgenic mouse lines overexpressing mTOR-activating ligands (IGF1 and FGF21) in most mTECs. Ongoing experiments aim to characterize the impact of increased paracrine mTOR signaling on age-associated thymic dysfunction. This work was supported by N.I.H. R21AI154109. Supported by grant from NIH (R21 AI154109)