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

This study systematically 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. The findings offer potential immunomodulatory strategies for regenerative medicine applications.

 

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 comprehensively analyzes how age-related immune changes compromise regenerative biomaterial efficacy, particularly through type 3 immune response suppression of tissue repair. The study highlights abnormal T cell-stromal communication in aging microenvironments and demonstrates therapeutic potential through IL17-targeted interventions to restore regenerative capacity.

Background Knowledge
With advancing age, declining tissue repair capacity correlates with immunological changes. Age-related T-cell composition alterations 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). Additionally, senescent cells (SnCs) accumulating in aged tissues promote inflammation and fibrosis through senescence-associated secretory phenotype (SASP) secretion, 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 the knowledge gap by systematically analyzing age-induced immune-stromal communication impairment and proposing IL17-targeted therapeutic strategies.

 

 

Research Methods and Experiments
Young (6-week) and aged (72-week) mouse models were employed to evaluate immune responses and tissue repair through muscle injury and ECM (small intestinal mucosa matrix) implantation. Multiparameter flow cytometry, single-cell RNA sequencing (scRNA-seq), and Domino computational analysis characterized cellular communication patterns across age groups. IL17 neutralizing antibodies and senolytic drug ABT263 were administered to modulate immune responses and assess 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.
• Age-related immune skewing is evident in aged animals with significant reductions in Th2 cells and eosinophils, alongside increased Th17 and CD8+T cells.
• Domino analysis identifies Igf1 and Tgfβ3 signaling through Batf and Crem transcription factors promoting Th17 differentiation in aged tissues, contrasting with Th2-dominant signaling in young mice.
• IL17 neutralizing antibodies (αIL17A or αIL17F) restore Th2 immune responses in aged mice, increasing IL4+ cell proportions and improving muscle repair.
• Combined ECM biomaterials with αIL17 antibodies significantly reduce fibrosis- and adipogenesis-related gene expression (Col3a1, Col5a1, Pparγ), restoring muscle regeneration.
• Senescent cell clearance (ABT263) decreases Il17a expression in lymph nodes, suggesting positive feedback between senescent cells and Th17 cells.

Research Significance and Prospects
This study provides the first systematic analysis of aging-induced communication failure between T cells and stromal cells compromising regenerative medicine efficacy. It establishes novel immunomodulatory approaches for age-related tissue repair disorders. Future research should investigate Batf and Crem functions in human aging diseases and explore clinical translation potential of combined senolytic and IL17-targeting strategies.

 

 

Conclusion
Advanced age dramatically alters immune-stromal communication networks, diminishing regenerative therapy responses. Single-cell transcriptomics reveal Th17-skewed T-cell signaling in aged mice that can be partially reversed through IL17 neutralization, restoring Th2-mediated tissue repair. These findings establish new immunomodulatory therapeutic directions for regenerative medicine and highlight the therapeutic value of targeting age-related signaling pathways (Batf, Crem, Tgfβ3). Future studies should optimize IL17-targeting strategies and explore human translation potential for 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.).