Defects in skin γδ T cell function contribute to delayed wound repair in rapamycin-treated mice

Disruptions in the normal program of tissue repair can result in poor wound healing, which perturbs the integrity of barrier tissues such as the skin. Such defects in wound repair occur in transplant recipients treated with the immunosuppressant drug rapamycin (sirolimus). Intraepithelial lymphocytes, such as gamma delta T cells in the skin, mediate tissue repair through the production of cytokines and growth factors. The capacity of skin-resident T cells to function during rapamycin treatment was analyzed in a mouse model of wound repair. Rapamycin treatment renders skin gamma delta T cells unable to proliferate, migrate, and produce normal levels of growth factors. The observed impairment of skin gamma delta T cell function is directly related to the inhibitory action of rapamycin on mammalian target of rapamycin. Skin gamma delta T cells treated with rapamycin are refractory to IL-2 stimulation and attempt to survive in the absence of cytokine and growth factor signaling by undergoing autophagy. Normal wound closure can be restored in rapamycin-treated mice by addition of the skin gamma delta T cell-produced factor, insulin-like growth factor-1. These studies not only reveal that mammalian target of rapamycin is a master regulator of gamma delta T cell function but also provide a novel mechanism for the increased susceptibility to nonhealing wounds that occurs during rapamycin administration.