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

This study reveals the critical role of aging and T cell signaling in Type 3 immune responses, demonstrating that IL-17 neutralizing antibodies can restore muscle repair capabilities in aged animals, offering potential therapeutic strategies for regenerative medicine.

 

Literature Overview
This study 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 changes affect regenerative biomaterial efficacy, particularly through Type 3 immune suppression of tissue repair. It emphasizes abnormal T cell-stromal communication in the aging microenvironment and highlights the therapeutic potential of targeting IL-17 to restore regenerative capacity.

Background Knowledge
Tissue repair capacity declines with age, closely linked to immune system alterations. Age-related T cell changes in individuals include increased CD8+ T cells, decreased CD4+ T cells, and elevated Th17 cell proportions, which may impair regenerative immune responses (e.g., Th2-mediated repair). Senescent cells (SnCs) accumulating in aged tissues promote inflammation and fibrosis through senescence-associated secretory phenotypes (SASPs), further inhibiting repair. While age-related immune changes have been studied in infection, vaccination, and cancer immunotherapy contexts, their impact on regenerative medicine remains unclear. This work fills this gap by systematically analyzing aging-induced immune-stromal communication disruptions and proposing IL-17-targeted therapeutic strategies.

 

 

Research Methods and Experiments
Using young (6-week) and aged (72-week) murine models, the research team evaluated immune and tissue repair responses through muscle injury and ECM (small intestinal submucosa) implantation. Multi-parameter flow cytometry, single-cell RNA sequencing (scRNA-seq), and Domino computational analysis assessed cellular communication patterns across age groups. IL-17 neutralizing antibodies and senolytic drug ABT263 were employed to modulate immune responses and evaluate tissue repair outcomes.

Key Conclusions and Perspectives

• Aged mice exhibit enhanced Type 3 immune responses (Il17f expression) and elevated senescent cell markers (p16INK4a) following muscle injury.
• Older animals show significant reductions in Th2 cell and eosinophil proportions with increased Th17 and CD8+ T cells, indicating age-associated immune polarization.
• Domino analysis reveals Igf1 and Tgfβ3 signaling through Batf and Crem transcription factors promotes Th17 differentiation in aged tissues, whereas Th2-associated signals dominate in young mice.
• IL-17 neutralizing antibodies (αIL17A or αIL17F) restore Th2 immune responses in aged mice, increasing IL4+ cell proportions and improving muscle repair.
• Combined ECM biomaterials and αIL17 antibody treatment significantly reduce fibrosis- and adipogenesis-related gene expression (e.g., Col3a1, Col5a1, Pparγ), restoring 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 elucidates how aging compromises regenerative medicine efficacy through T cell-stromal communication deficits, providing novel insights for developing immunomodulatory therapies for age-related tissue repair disorders. Future research should investigate Batf and Crem roles in human aging-related diseases and explore clinical translation potential of combined senolytic and IL-17-targeting approaches.

 

 

Conclusion
Aging dramatically alters immune-stromal communication networks, leading to diminished regenerative responses. Single-cell transcriptomic analyses reveal Th17 polarization in aged mice T cell signaling, while IL-17 neutralizing antibodies partially restore Th2-mediated tissue repair. These findings provide new directions for immunomodulatory therapies in regenerative medicine and highlight therapeutic value of targeting aging-related signaling pathways (e.g., Batf, Crem, Tgfβ3). Future studies should optimize IL-17 targeting strategies and explore their translational potential in human tissue repair.

 

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.).