Functional tendon regeneration is driven by regulatory T cells and IL-33 signaling
Varun Arvind, Giulia Crosio, Kristen Howell, Hui Zhang, Angela M. Montero, Alice H. Huang
Abstract
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.