Advanced Materials | Age-associated Senescent T Cell Signaling Promotes Type 3 Immunity and Inhibits Biomaterial Regenerative Response

This study elucidates the critical role of senescent T cell signaling in age-related type 3 immune responses and demonstrates that IL17 neutralizing antibodies can restore muscle repair capacity in aged animals, providing potential therapeutic strategies for regenerative medicine.

 

Literature Overview
This article titled 'Age-associated Senescent - T Cell Signaling Promotes Type 3 Immunity that Inhibits the Biomaterial Regenerative Response' published in Advanced Materials reviews how age-related immune alterations affect regenerative biomaterial efficacy, particularly through type 3 immune suppression of tissue repair. The study emphasizes aberrant communication between T cells and stromal cells in the aging microenvironment, while highlighting therapeutic potential of targeting IL17 to restore regenerative capacity.

Background Knowledge
As organisms age, tissue repair capacity declines, closely associated with immune system alterations. Research shows that aging leads to shifts in T cell composition including increased CD8+T cells, decreased CD4+T cells, and elevated Th17 cell proportions, which may impair regenerative immune responses (e.g., Th2-mediated repair). Additionally, senescent cells (SnCs) accumulating in aged tissues promote inflammation and fibrosis through secretion of senescence-associated secretory phenotypes (SASP), further hindering tissue repair. While age-related immune changes have been studied in contexts of infection, vaccination, and cancer immunotherapy, their impact on regenerative medicine remains unclear. This study fills this knowledge gap by systematically analyzing how aging affects immune-stromal communication and proposes targeted IL17 therapeutic strategies.

 

 

Research Methods and Experiments
The research team evaluated immune and tissue repair responses in young (6-week) and aged (72-week) murine models following muscle injury and extracellular matrix (ECM) scaffold implantation. Multiparameter flow cytometry, single-cell RNA sequencing (scRNA-seq), and Domino computational analysis were employed to characterize cellular communication patterns across age groups. Immune modulation was achieved through IL17 neutralizing antibodies and senescent cell clearance with ABT263, with subsequent assessment of tissue repair outcomes.

Key Conclusions and Perspectives

• Aged mice demonstrate enhanced type 3 immune responses (Il17f expression) and elevated senescent cell markers (p16INK4a) following muscle injury.
• Age-related immune skewing is evident in aged animals with significant reduction in Th2 cells and eosinophils, accompanied by increased Th17 and CD8+T cells.
• Domino analysis reveals that Igf1 and Tgfβ3 signaling through Batf and Crem transcription factors promotes Th17 differentiation in aged tissues, whereas young mice exhibit dominant Th2-associated signaling.
• IL17 neutralizing antibodies (αIL17A or αIL17F) restore Th2 immune responses in aged mice, increasing IL4+ cell populations and improving muscle repair.
• Combined ECM biomaterial and αIL17 antibody treatment significantly reduces fibrotic and adipogenic gene expression (e.g., Col3a1, Col5a1, Pparγ) while enhancing muscle regeneration.
• Senescent cell clearance via ABT263 decreases Il17a expression in lymph nodes, suggesting a positive feedback mechanism between senescent cells and Th17 cells.

Research Significance and Prospects
This study systematically defines how aging compromises regenerative medicine efficacy through T cell-stromal communication dysfunction, providing novel insights for developing immunomodulatory therapies targeting age-related tissue repair deficiencies. Future research should investigate Batf and Crem functions in human aging-related diseases and evaluate clinical translation potential of combined senescent cell targeting and IL17 inhibition.

 

 

Conclusion
Advanced age significantly disrupts communication networks between immune and stromal cells, resulting in diminished therapeutic responses to regenerative interventions. Single-cell transcriptomic analyses reveal Th17-skewed T cell signaling in aged mice, which can be partially reversed by IL17 neutralizing antibodies to restore Th2-mediated tissue repair. These findings establish new directions for immunomodulatory therapies in regenerative medicine and highlight the therapeutic importance of targeting age-associated signaling pathways (e.g., Batf, Crem, Tgfβ3). Future studies should focus on optimizing IL17-targeted strategies and exploring their translational potential in human tissue repair applications.

 

Jin Han, Christopher Cherry, Joscelyn C Mejías, Drew M Pardoll, and Jennifer H Elisseeff. Age-associated Senescent - T Cell Signaling Promotes Type 3 Immunity that Inhibits the Biomaterial Regenerative Response. Advanced materials (Deerfield Beach, Fla.).