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.