A dynamic paracrine FGF21-mTORC1/mTORC2 signaling axis regulates thymus function across the lifespan 3308

Abstract Description Thymic stromal cells (TSCs), particularly cortical thymic epithelial cells (cTECs), are the primary targets of age-associated thymic atrophy, but the mechanisms regulating thymic growth and atrophy remain relatively obscure. Recent studies characterizing the TSC transcriptional response to age-associated thymus atrophy and experimental regeneration suggested that growth factors expressed in medullary TECs (mTECs) drive paracrine mTOR signaling in cTECs to maintain their unique morphology, regulating thymus size. To test these hypotheses, we generated a bi-cistronic knock-in (KI) mouse model in which the mTOR-activating ligand FGF21 is expressed under the control of the Lactoperoxidase gene (LPOFGF21), directing expression broadly but specifically in mTECs in the thymus. mTEC-derived FGF21 overexpression promotes temporally distinct mTORC1 and mTORC2 signaling in cTECs, promotes thymus and individual cTEC growth and maintenance, increases T cell responsiveness to influenza, and diminishes indicators of peripheral autoimmunity in older mice. The effects of FGF21 overexpression on thymus size and mTOR signaling were abrogated by rapamycin treatment, consistent with a role for mTOR-mediated FGF21 signaling in cTEC growth and maintenance. These results reveal a novel molecular mechanism by which paracrine signaling regulates thymus size and function throughout the lifespan, as well as novel potential therapeutic targets for improving T cell function in the aging population. Funding Sources Supported by NIH R01AG086271 (A.V.G), R21AI154109 (A.V.G), and R21AG081709 (A.V.G); the DiGeorge Syndrome Research Fund (G.A.H.), Swiss National Science Foundation grant IZLJZ3_171050; 310030_184672 (G.A.H.), Medical Research Council grant MR/S036407/1 (G.A.H.), Wellcome Trust grant 105045/Z/14/Z, and 211944/Z/18/Z (G.A.H) Topic Categories Hematopoiesis and Immune System Development (HEM)