Reprogramming adult tendon healing using regenerative neonatal regulatory T cells

Abstract

ABSTRACTTendinopathy is a common clinical problem leading to significant musculoskeletal disability. Using a neonatal mouse model of tendon regeneration compared to adult tendon fibrosis, we identified a unique immune profile in regeneration that is associated with type 2 macrophage polarization and regulatory T cell (Treg) infiltration. Neonatal Treg ablation resulted in a dysregulated immune response leading to failed tenocyte recruitment and loss of functional regeneration. Transcriptional profiling of adult and neonatal tendon Tregs revealed distinct type 1 and type 2 immune signatures that facilitate macrophage polarization following injury. Finally, adoptive transfer of mouse and human neonatal Tregs was sufficient to improve functional regeneration, in contrast to adult Treg transfer. Collectively, these studies uncover a critical role for neonatal Tregs in controlling immune polarization to promote an environment permissive for tendon regeneration. Our findings provide a basis for immune modulating therapies to facilitate regenerative adult tendon healing.