Functional 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 regeneration. We showed that neonatal T(reg) cells mitigate interleukin-33 (IL-33) to enable tenocyte recruitment and structural restoration, and that adult IL-33 deletion improves functional healing. Collectively, these findings demonstrate that T(reg) cells and IL-33 immune dysfunction are critical components of failed tendon healing and identify potential targets to drive tendon regeneration.