Age‐associated Senescent – T Cell Signaling Promotes Type 3 Immunity that Inhibits the Biomaterial Regenerative Response
Jin Han, Christopher Cherry, Joscelyn C. Mejías, Kavita Krishnan, Anna Ruta, David R. Maestas, Alexis N. Peña, Helen Nguyễn, Sushma Nagaraj, Brenda Yang, Elise Gray-Gaillard, Natalie Rutkowski, Maria Browne, Ada Tam, Elana J. Fertig, Franck Housseau, Sudipto Ganguly, Erika Moore, Drew M. Pardoll, Jennifer H. Elisseeff
Abstract
Aging is associated with immunological changes that compromise response to infections and vaccines, exacerbate inflammatory diseases and can potentially mitigate tissue repair. Even so, age-related changes to the immune response to tissue damage and regenerative medicine therapies remain unknown. Here, it is characterized how aging induces changes in immunological signatures that inhibit tissue repair and therapeutic response to a clinical regenerative biological scaffold derived from extracellular matrix. Signatures of inflammation and interleukin (IL)-17 signaling increased with injury and treatment both locally and regionally in aged animals, and computational analysis uncovered age-associated senescent-T cell communication that promotes type 3 immunity in T cells. Local inhibition of type 3 immune activation using IL17-neutralizing antibodies improves healing and restores therapeutic response to the regenerative biomaterial, promoting muscle repair in older animals. These results provide insights into tissue immune dysregulation that occurs with aging that can be targeted to rejuvenate repair.