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RANKL treatment restores thymic function and improves T cell-mediated immune responses in aged mice.
Jérémy C Santamaria1, Jessica Chevallier1, Léa Dutour2
1Centre d'Immunologie de Marseille-Luminy, CIML, CNRS, INSERM, Aix-Marseille Université, Marseille, Turing Centre for Living Systems, 13288 Marseille Cedex 09, France.
Science Translational Medicine
|December 4, 2024
Summary
Aging impairs thymus function, reducing T cell production and immunity. Restoring the RANK-RANKL pathway with exogenous RANKL rejuvenates the aged thymus, boosting T cell immunity and vaccine responses.
Area of Science:
- Immunology
- Aging Research
- Cell Biology
Background:
- Age-related thymic involution leads to immunosenescence, increasing susceptibility to diseases and reducing vaccine efficacy.
- The receptor activator of nuclear factor κB (RANK)-RANK ligand (RANKL) axis in the thymus is altered during aging, impacting thymic epithelial and endothelial cells.
Purpose of the Study:
- To investigate the role of the RANK-RANKL axis in age-related thymic involution.
- To explore the therapeutic potential of targeting the RANK-RANKL axis to restore thymic function in aged individuals.
Main Methods:
- Utilized a conditional transgenic mouse model to study RANK signaling in endothelial cells.
- Administered exogenous RANKL to aged mice and assessed thymic architecture, cell populations, and T cell production.
- Conducted a proof-of-concept study using human thymic organocultures.
Main Results:
- Decreased RANKL availability during aging impairs endothelial and thymic epithelial cell function, contributing to thymic involution.
- Exogenous RANKL treatment in aged mice restored thymic architecture, improved endothelial and epithelial cell abundance and function, and enhanced T cell production.
- RANKL administration promoted T cell progenitor homing, peripheral T cell renewal, and improved antitumor and vaccine responses in aged mice.
Conclusions:
- The RANK-RANKL axis is crucial for maintaining thymic function during aging.
- Targeting the RANK-RANKL axis with exogenous RANKL is a promising therapeutic strategy to rejuvenate thymic function and enhance T cell immunity in the elderly.
