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, 'Age-associated Senescent - T Cell Signaling Promotes Type 3 Immunity that Inhibits the Biomaterial Regenerative Response' published in Advanced materials, systematically reviews how age-related immune changes impair therapeutic efficacy of regenerative biomaterials, particularly through Type 3 immune-mediated suppression of tissue repair. The study highlights abnormal T cell-stromal communication in the aging microenvironment and the therapeutic potential of targeting IL17 to restore regenerative capacity.

Background Knowledge
Age-related decline in tissue repair capacity correlates with immune system alterations. Established findings show that aging individuals exhibit shifts in T cell composition, including increased CD8+T cells, decreased CD4+T cells, and elevated Th17 cell proportions, which may compromise 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) factors, further impairing repair processes. 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 critical knowledge gap by systematically analyzing how aging affects immunostromal 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 evaluate immune responses and tissue repair through muscle injury and ECM (small intestinal submucosa) implantation. Multiparametric flow cytometry, single-cell RNA sequencing (scRNA-seq), and Domino computational analysis were applied to investigate cell communication patterns across age groups. IL17 neutralizing antibodies and senolytic drug ABT263 were further utilized to modulate immune responses and assess their effects on tissue regeneration.

Key Conclusions and Perspectives

• Aged mice demonstrate enhanced Type 3 immune responses (elevated Il17f expression) and increased senescent cell markers (p16INK4a) after muscle injury.
• Aged animals exhibit significant reduction in Th2 cells and eosinophils, with corresponding increases in Th17 and CD8+T cells, indicating age-related immunological polarization.
• Domino analysis reveals that Igf1 and Tgfβ3 signals promote Th17 differentiation via Batf and Crem transcription factors in aged tissues, whereas Th2-associated signals predominate in young mice.
• IL17 neutralizing antibodies (αIL17A or αIL17F) restore Th2 immune responses in aged mice, increase IL4+ cell proportions, and improve muscle repair outcomes.
• Combined ECM biomaterials with αIL17 antibodies significantly reduce fibrosis- and adipogenesis-related gene expression (e.g., Col3a1, Col5a1, Pparγ) and rejuvenate muscle regeneration.
• Senescent cell clearance using ABT263 decreases Il17a expression in lymph nodes, suggesting a positive feedback loop between senescent cells and Th17 cells.

Research Significance and Prospects
This study represents the first systematic analysis of aging-induced communication failure between immune and stromal cells compromising regenerative medicine efficacy, offering novel insights for developing immunomodulatory therapies targeting age-related tissue repair dysfunction. Future research should investigate Batf and Crem mechanisms in human aging-related diseases and evaluate clinical translation potential of combined senolytic and IL17-targeted approaches.

 

 

Conclusion
Aging fundamentally alters immunostromal communication networks, diminishing regenerative therapy responses. Single-cell transcriptomic analyses reveal Th17 polarization in aged mice T cell signaling, while IL17 neutralizing antibodies partially restore Th2-mediated tissue repair. These findings establish 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 IL17-targeted strategies and explore their translational potential in human tissue regeneration.

 

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.).