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

Abstract

Abstract The thymus is the primary site of T cell generation, where the unique thymic stromal microenvironment governs T cell differentiation. 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. Preventing or reversing age-associated thymic atrophy therefore holds potential for extending the health span. Mechanisms governing thymic atrophy have been difficult to identify because the primary targets of atrophy, cortical thymic epithelial cells (cTECs), are rare and difficult to isolate. Characterization of the transcriptional response of thymic stromal cells during age-related atrophy and experimental regeneration 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 growth factors (IGF1 and FGF21) in most mTECs. Ongoing flow cytometry and confocal microscopy experiments indicate faithful transgene expression in mTECs, and suggest that mTEC-derived growth factors promote temporally distinct patterns of mTORC1 and mTORC2 signaling in cTECs to promote thymus growth and maintenance with age. This work was supported by NIH R21AI154109 and T32 AI138944-05. Supported by grants from NIH (R21 AI154109, T32 AI138944-05)