biostudies-literatureArvind VNIAMS NIH HHSNIGMS NIH HHSeadn5409https://www.ebi.ac.uk/biostudies/studies/S-EPMC12017337biostudies-literatureUnknown11(17)Tendon injuries heal by scar, leading to poor function. To date, the role of immune cells remains underexplored. Using a neonatal mouse model of functional tendon healing compared to adult scar-mediated healing, we identified a regenerative immune profile that is associated with type 1 inflammation followed by rapid polarization to type 2, driven by macrophages and regulatory T cells (T_reg cells). Single-cell and bulk RNA sequencing also revealed neonatal T_reg cells with an immunomodulatory signature distinct from adult. Neonatal T_reg cell ablation resulted in a dysregulated immune response, failed tenocyte recruitment, and impaired regeneration. Adoptive transfer further confirmed the unique capacity of neonatal T_reg cells to rescue functional rScience advancesFunctional tendon regeneration is driven by regulatory T cells and IL-33 signaling.PMC12017337R56 AR076984R01 AR069537R01 AR081674F31 AR076905T32 GM007280Crosio GZhang HMontero AArvind VHowell KHuang AHfalseFunctional tendon regeneration is driven by regulatory T cells and IL-33 signaling.Tendon injuries heal by scar, leading to poor function. To date, the role of immune cells remains underexplored. Using a neonatal mouse model of functional tendon healing compared to adult scar-mediated healing, we identified a regenerative immune profile that is associated with type 1 inflammation followed by rapid polarization to type 2, driven by macrophages and regulatory T cells (T_reg cells). Single-cell and bulk RNA sequencing also revealed neonatal T_reg cells with an immunomodulatory signature distinct from adult. Neonatal T_reg cell ablation resulted in a dysregulated immune response, failed tenocyte recruitment, and impaired regeneration. Adoptive transfer further confirmed the unique capacity of neonatal T_reg cells to rescue functional r2025-01-01T00:00:00Z2025 Apr2026-06-02T04:13:08.803Z2025-07-06T03:04:32.012ZS-EPMC120173374026720610.1126/sciadv.adn5409