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Published on: March 25, 2020
Defects in skin gamma delta T cell function contribute to delayed wound repair in rapamycin-treated mice
Robyn E Mills1, Kristen R Taylor, Katie Podshivalova
1Department of Immunology, The Scripps Research Institute, La Jolla, CA 92037, USA.
Abstract:
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 gammadelta 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 gammadelta T cells unable to proliferate, migrate, and produce normal levels of growth factors. The observed impairment of skin gammadelta T cell function is directly related to the inhibitory action of rapamycin on mammalian target of rapamycin. Skin gammadelta 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 gammadelta T cell-produced factor, insulin-like growth factor-1. These studies not only reveal that mammalian target of rapamycin is a master regulator of gammadelta T cell function but also provide a novel mechanism for the increased susceptibility to nonhealing wounds that occurs during rapamycin administration.
Insights
Rapamycin impairs skin gammadelta T cell function, hindering wound repair by inhibiting mTOR. Restoring insulin-like growth factor-1 can improve healing in mice treated with this immunosuppressant.
Area of Science:
- Immunology
- Dermatology
- Wound Healing Research
Background:
- Impaired wound healing is a clinical challenge, particularly in immunosuppressed patients.
- Rapamycin (sirolimus) treatment can disrupt tissue repair, affecting skin integrity.
- Intraepithelial lymphocytes, like skin gammadelta T cells, are crucial for tissue repair via cytokine and growth factor production.
Purpose of the Study:
- To investigate the functional impact of rapamycin on skin gammadelta T cells during wound repair.
- To elucidate the underlying molecular mechanisms of rapamycin-induced impairment in skin gammadelta T cell function.
- To identify potential therapeutic strategies to restore wound healing in rapamycin-treated individuals.
Main Methods:
- Utilized a mouse model of skin wound repair.
- Analyzed the proliferation, migration, and cytokine production of skin gammadelta T cells under rapamycin treatment.
- Investigated the role of mammalian target of rapamycin (mTOR) signaling and autophagy in rapamycin-affected T cells.
- Assessed the efficacy of insulin-like growth factor-1 in restoring wound closure.
Main Results:
- Rapamycin treatment significantly inhibited the proliferation, migration, and growth factor production of skin gammadelta T cells.
- The observed functional impairment was directly linked to the inhibition of mammalian target of rapamycin (mTOR) signaling.
- Rapamycin-treated skin gammadelta T cells exhibited refractoriness to IL-2 stimulation and increased autophagy for survival.
- Addition of insulin-like growth factor-1 successfully restored normal wound closure in rapamycin-treated mice.
Conclusions:
- Mammalian target of rapamycin (mTOR) is a critical regulator of gammadelta T cell function in skin repair.
- Rapamycin disrupts wound healing by impairing gammadelta T cell-mediated repair mechanisms.
- Targeting mTOR signaling or supplementing with factors like insulin-like growth factor-1 may offer therapeutic benefits for nonhealing wounds in patients on rapamycin.
