Advanced materials | Age-associated Senescent T Cell Signaling Promotes Type 3 Immune Responses and Inhibits Biomaterial Regenerative Responses

This study reveals the critical role of aging and T cell signaling in Type 3 immune responses, demonstrating that IL17 neutralizing antibodies can restore muscle repair capabilities in aged animals, providing potential therapeutic strategies for regenerative medicine.

 

Literature Overview
The article '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 changes affect therapeutic outcomes of regenerative biomaterials, particularly through Type 3 immune suppression of tissue repair. The research emphasizes abnormal T cell-stromal communication in the aging microenvironment and highlights the therapeutic potential of targeting IL17 to restore regenerative capacity.

Background Knowledge
Tissue repair capacity declines with aging, closely linked to immune system alterations. Studies show age-related changes in T cell composition in elderly individuals, 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 senescence-associated secretory phenotypes (SASP), further hindering tissue repair. While age-related immune changes have been explored in contexts like infection, vaccination, and cancer immunotherapy, their impact on regenerative medicine remains unclear. This study fills this gap by systematically analyzing how aging affects immune-stromal communication and proposing targeted IL17 therapeutic strategies.

 

 

Research Methods and Experiments
The research team employed young (6-week) and aged (72-week) murine models to assess immune and tissue repair responses following muscle injury and extracellular matrix (ECM) implantation. Multi-parameter flow cytometry, single-cell RNA sequencing (scRNA-seq), and Domino computational analysis were used to characterize cellular communication patterns across age groups. Additionally, immune responses were modulated using IL17 neutralizing antibodies and senolytic drug ABT263 to evaluate their effects on tissue repair.

Key Conclusions and Perspectives

• Aged mice exhibited enhanced Type 3 immune responses (Il17f expression) and increased senescent cell markers (p16INK4a) following muscle injury.
• Significant reductions in Th2 cells and eosinophils were observed in aged animals, alongside increased Th17 and CD8+ T cells, indicating age-associated immune polarization.
• Domino analysis revealed that Igf1 and Tgfβ3 signaling through Batf and Crem transcription factors promoted Th17 differentiation in aged tissues, whereas Th2-associated signaling dominated in young mice.
• IL17 neutralizing antibodies (αIL17A or αIL17F) restored Th2 immune responses in aged mice, increased IL4+ cell proportions, and improved muscle repair.
• Combined ECM biomaterials with αIL17 antibody treatment significantly reduced fibrosis- and adipogenesis-related gene expression (e.g., Col3a1, Col5a1, Pparγ) and restored muscle regeneration.
• Senescent cell clearance via ABT263 reduced Il17a expression in lymph nodes, suggesting a positive feedback mechanism between senescent cells and Th17 cells.

Research Significance and Prospects
This study pioneers the systematic analysis of aging-induced communication defects between T cells and stromal cells that compromise regenerative medicine efficacy, offering novel insights for developing immune-modulatory therapies for age-related tissue repair deficiencies. Future research should investigate Batf and Crem roles in human aging-related diseases and explore clinical translation potential of combined senescent cell targeting and IL17 inhibition.

 

 

Conclusion
Advancing age fundamentally alters communication networks between immune and stromal cells, diminishing regenerative therapy responses. Single-cell transcriptomic analysis reveals Th17-polarized T cell signaling in aged mice, while IL17 neutralization partially restores Th2-mediated tissue repair. These findings establish new directions for immunomodulatory therapies in regenerative medicine and underscore the therapeutic value of targeting age-related signaling pathways (e.g., Batf, Crem, Tgfβ3). Future studies should optimize IL17-targeting strategies and evaluate 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.).