PROJECT SUMMARY Tendon injury is a common problem characterized by slow recovery and high recurrence. Improving tendon healing to a regenerative state is therefore a crucial research priority, however the basic biological mechanisms remain unknown. Our overall objective is therefore to identify the cellular and molecular events that distinguish tenogenic regeneration vs fibrosis to improve adult tendon healing. One key feature in all wound healing is the immune environment. Injury initially induces an inflammatory type 1 response, followed by transition to an anti-inflammatory type 2 response. Imbalanced type 1 or type 2 responses are often associated with fibrotic healing or degeneration. To date, adaptive immune cells have rarely been investigated, even though T cell subpopulations regulate type 1 and type 2 immune responses, macrophage polarization, and in some cases can directly active tissue-resident stem cells. Due to this gap in research, the mechanisms by which specific immune cell populations create permissive environments for regeneration vs fibrosis are not known, especially for normally non-regenerative tissues such as tendon. We recently established novel models of functional tendon regeneration (neonatal mouse) and fibrosis (adult mouse), and identified cellular mechanisms that distinguish regeneration from fibrosis. We now propose that neonatal immune cells and the immune environment are crucial for tendon regeneration. To test this hypothesis, we will characterize the immune landscape during healing, determine the requirement of specific T cells in healing using loss and gain of function experiments, and determine the role of IL33 signaling in adult tendon healing. Successful completion will establish the immune response underlying tendon healing and identify a new and exciting role for T cells and IL33 signaling in tendon regeneration and fibrosis, respectively.