Age-Associated Senescent T Cell Signaling Promotes Type III Immunity that Inhibits Regenerative Biomaterial Responses

This study systematically elucidates how aging-related T cell signaling enhances type III immune responses, thereby suppressing the efficacy of regenerative biomaterials. By demonstrating that IL17 neutralizing antibodies can restore regenerative responses, it provides novel immunomodulatory strategies for regenerative medicine.

 

Literature Overview
The article 'Age-associated Senescent T Cell Signaling Promotes Type III Immunity that Inhibits the Biomaterial Regenerative Response' published in Advanced Materials reviews the impact of aging on tissue repair and regenerative biomaterial therapy. Using multi-omics analysis and animal models, the study reveals aging-induced immune microenvironment alterations, particularly enhanced type III immunity and suppressed regenerative biomaterial efficacy.

Background Knowledge
Aging causes significant immune system changes, including T cell dysfunction, inflammatory cytokine accumulation, and increased senescent cells (SnCs), all linked to diminished tissue repair capacity. The research utilized extracellular matrix (ECM) biomaterials derived from porcine small intestinal submucosa to simulate clinical regenerative therapies. While ECM treatment effectively promoted muscle repair in young mice (6 weeks), it failed to activate regenerative immune responses in aged mice (72 weeks). The study further identified elevated type III immunity (IL17-mediated) and suppressed type II immunity (IL4-driven) in aged mice, leading to increased fibrosis and adipogenesis. IL17 neutralizing antibody treatment partially restored muscle repair in aged mice. Single-cell RNA sequencing and computational analyses revealed altered T cell-stromal communication in aging environments, providing a theoretical foundation for developing targeted immunotherapies for regenerative medicine.

 

 

Research Methods and Experiments
Young (6-week) and aged (72-week) female mice were established with muscle injury models to evaluate immune and repair responses following ECM biomaterial implantation. Cellular composition and gene expression changes across age groups were analyzed using multi-parameter spectral flow cytometry and single-cell RNA sequencing (scRNA-seq). The Domino algorithm mapped intercellular communication networks, complemented by Bayesian non-negative matrix factorization (CoGAPS) for gene expression pattern analysis. The effects of IL17 neutralization and senescent cell clearance on muscle repair were systematically assessed.

Key Conclusions and Perspectives

• Il17f gene expression is significantly elevated while Il4 expression is reduced in aged mice after muscle injury or ECM implantation, indicating enhanced type III immunity and impaired type II immunity.
• Il17a expression in γδ T cells and CD4 T cells increases in aged mice, with significant upregulation of Th17 cytokines (e.g., Mmp3, Mmp9, Cxcl1) post-injury, highlighting type III immunity's dominant role in aging.
• Domino analysis reveals elevated IGF1 and TGFβ3 signaling in aged muscle, promoting Th17 differentiation through Batf and Crem transcription factors to suppress regeneration.
• IL17 neutralizing antibody treatment restores Il4 expression and muscle repair capacity in aged mice, reduces fibrosis and adipogenesis, demonstrating that blocking type III immunity reverses age-related regenerative impairments.
• Senescent cell clearance decreases Il17a expression in lymph nodes and improves the immune microenvironment, restoring ECM's regenerative potential.

Research Significance and Prospects
This study pioneers the systematic demonstration of aging-induced suppression of biomaterial efficacy through enhanced type III immunity and altered T cell-stromal communication. It identifies novel therapeutic targets for regenerative medicine, such as combining IL17 inhibition with biomaterials to enhance tissue repair in elderly patients. Future research should explore Batf and Crem as potential targets and develop personalized immunomodulatory strategies tailored to aging microenvironments to improve clinical outcomes of regenerative therapies.

 

 

Conclusion
This systematic analysis demonstrates that aging suppresses biomaterial-induced regeneration through aberrant activation of type III immune responses. The Batf and Crem transcription factors mediate Th17 differentiation, promoting fibrosis and adipogenesis while inhibiting type II immunity and muscle repair. IL17 neutralizing antibodies or senescent cell clearance effectively restore muscle regeneration in aged mice, providing novel immunomodulatory targets and combination therapies for regenerative medicine. These findings offer critical theoretical support for developing personalized regenerative therapies for elderly populations and emphasize the importance of age-related immune microenvironment regulation in future research.

 

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.).