The role of T cells in tendon healing

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PROJECT SUMMARY Tendon injury is a common problem characterized by slow recovery and high recurrence. Improving tendon healing to a functionally effective 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 healing mechanisms 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, T 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 effective and poor healing are not known, especially for poor healing tissues such as tendon. We previously established novel models of effective tendon healing (neonatal mouse) and fibrosis (adult mouse), and identified cellular mechanisms that distinguish these. Based on rigorous pilot data, we now hypothesize that T cell subpopulations mediate tendon healing through direct and indirect interactions with tenocytes and by mediating effective tendon healing or chronic inflammation via IL33- dependent mechanisms. To test these hypotheses, we will define the role of neonatal vs adult T cell populations and T cell-tenocyte interactions after tendon injury (Aim 1), elucidate the mechanisms of Treg- mediated resolution of IL33 in tendon healing (Aim 2), and determine the pathological consequences of chronic IL33 inflammation in tendon healing (Aim 3)