Paracrine FGF21 dynamically modulates mTOR signaling to regulate thymus function across the lifespan

Area of Science:

• Immunology
• Aging Research
• Cell Biology

Background:

• Age-associated thymic atrophy leads to reduced T-cell function and impaired self-tolerance.
• Cortical thymic epithelial cells (cTECs) are crucial for T-cell development and are affected by thymic aging.
• mTOR signaling, downstream of medullary TEC (mTEC)-derived factors, is implicated in cTEC maintenance.

Purpose of the Study:

• To investigate the role of mTEC-derived FGF21 in regulating thymus size and function during aging.
• To determine the impact of FGF21 on mTOR signaling pathways within cTECs.
• To assess the effects of FGF21 on T-cell responsiveness and autoimmunity in aged mice.

Main Methods:

• Generated a knock-in mouse model expressing FGF21 and mCherry in mTECs.
• Administered the mTOR inhibitor rapamycin to assess its effect on FGF21-mediated signaling.
• Evaluated thymus size, cTEC maintenance, T-cell responses to viral infection, and indicators of peripheral autoimmunity.

Main Results:

• mTEC-derived FGF21 promoted distinct mTORC1 and mTORC2 signaling patterns in cTECs.
• FGF21 overexpression led to increased thymus and cTEC size and improved maintenance.
• Enhanced T-cell responsiveness to viral infection and reduced autoimmunity were observed in older mice.
• Rapamycin treatment abrogated the effects of FGF21 on thymus size and mTOR signaling.

Conclusions:

• Paracrine FGF21 signaling is a key regulator of thymus size and function across the lifespan.
• FGF21 influences T-cell immunity and self-tolerance by modulating mTOR signaling in cTECs.
• Targeting FGF21-mTOR pathways presents a potential therapeutic strategy for age-related immune dysfunction.