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Single-cell RNA sequencing of thymic EC and TEC from control and RANKL treated aged mice

ABSTRACT: Age-related thymic involution is one of the major causes of immunosenescence, characterized by reduced production of naive T cells, leading to increased susceptibility to cancers, infections, autoimmunity and reduced vaccine efficacy. Here, we reveal that the RANK/RANKL axis is altered in the thymus during aging, which results in a decline in thymic epithelial cell (TEC) and endothelial cell (EC) function and, consequently, to thymic involution. Whereas RANKL neutralization in young mice mimics thymic involution, RANKL treatment in aged individuals restores the thymic architecture, TEC and EC functional properties, and thymic T-cell production. This cascade of events results in peripheral T cell renewal and effective anti-tumor and anti-viral immune responses. Furthermore, we provide the proof-of-concept that RANKL stimulates TEC and EC in human thymic organo-cultures. Collectively, our findings identify RANKL administration as a potent therapeutic strategy to rejuvenate thymic function and improve T-cell immune function in the elderly.

ORGANISM(S): Mus musculus

PROVIDER: GSE241880 | GEO | 2024/09/30

REPOSITORIES: GEO

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Single-cell RNA sequencing of thymic EC and TEC from control and RANKL treated aged mice

Project description:Single-cell RNA sequencing of thymic EC and TEC from control and RANKL treated aged mice

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Project description:The thymus is essential for establishing adaptive immunity yet undergoes age-related involution that leads to compromised immune responsiveness. The thymus is also extremely sensitive to acute insult and although capable of regeneration, this capacity declines with age for unknown reasons. We applied single-cell and spatial transcriptomics, lineage-tracing and advanced imaging to define age-related changes in non-hematopoietic stromal cells and discovered the emergence of two atypical thymic epithelial cell (TEC) states. These age-associated (aa)TECs formed high-density peri-medullary epithelial clusters that were devoid of thymocytes; an accretion of non-productive thymic tissue that worsened with age, exhibited features of epithelial-to-mesenchymal transition (EMT), and was associated with downregulation of FOXN1. Interaction analysis revealed that the emergence of aaTEC drew tonic signals from other functional TEC populations at baseline acting as a sink for TEC growth factors. Following acute injury, aaTEC expanded substantially, further perturbing trophic regeneration pathways and correlating with defective repair of the involuted thymus. These findings therefore define a unique feature of thymic involution linked to immune aging and could have implications for developing immune boosting therapies in older individuals.

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