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

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

 

Literature Overview
This study, 'Age-associated Senescent - T Cell Signaling Promotes Type 3 Immunity that Inhibits the Biomaterial Regenerative Response' published in Advanced materials, reviews age-related immune changes affecting regenerative biomaterial efficacy, particularly through type 3 immunity suppression of tissue repair. It highlights abnormal T cell-stromal communication in aging microenvironments and therapeutic potential of targeting IL-17 to restore regenerative capacity.

Background Knowledge
Tissue repair capacity declines with aging, closely linked to immune system alterations. Research shows age-related T cell composition changes 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 (SASP), further hindering repair. While age-related immune changes have been studied in infection, vaccination, and cancer immunotherapy contexts, their impact on regenerative medicine remains unclear. This study fills this knowledge gap by systematically analyzing how aging affects immune-stromal communication and proposing targeted IL-17 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 through muscle injury and ECM (small intestinal mucosal matrix) implantation. Multiparametric flow cytometry, single-cell RNA sequencing (scRNA-seq), and Domino computational analysis were employed to investigate cellular communication patterns across age groups. Additionally, tissue repair outcomes were assessed following IL-17 neutralizing antibody interventions and senescent cell clearance using ABT263.

Key Conclusions and Perspectives

• Aged mice exhibit 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 reductions in Th2 cells and eosinophils, accompanied by increased Th17 and CD8+ T cells.
• Domino analysis identified Igf1 and Tgfβ3 signaling through Batf and Crem transcription factors promoting Th17 differentiation in aged tissues, contrasting with Th2-dominant signaling in young mice.
• IL-17 neutralizing antibodies (αIL-17A or αIL-17F) restored Th2 immune responses in aged mice, increasing IL4+ cell proportions and improving muscle repair.
• Combined ECM biomaterial and αIL-17 antibody treatment significantly reduced fibrosis- and adipogenesis-related gene expression (e.g., Col3a1, Col5a1, Pparγ), restoring muscle regeneration.
• Senescent cell clearance via ABT263 decreased Il17a expression in lymph nodes, suggesting a positive feedback mechanism between senescent cells and Th17 cells.

Research Significance and Prospects
This study provides the first systematic analysis of how aging compromises regenerative medicine efficacy through T cell-stromal communication dysfunction, offering new immunomodulatory therapeutic avenues for age-related tissue repair disorders. Future research should investigate Batf and Crem roles in human aging diseases and explore clinical translation of combined senescent cell/IL-17 targeting strategies.

 

 

Conclusion
Aging substantially alters immune-stromal communication networks, diminishing regenerative therapy responses. Single-cell transcriptomics revealed Th17-skewed T cell signaling in aged mice, with IL-17 neutralizing antibodies partially restoring Th2-mediated tissue repair. These findings establish new immunomodulatory directions for regenerative medicine and highlight therapeutic value of targeting age-related signaling pathways (Batf, Crem, Tgfβ3). Future studies should optimize IL-17 targeting strategies and explore human translational 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.).