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Defects in Skin T Cell Function Contribute to Delayed Wound Repair in Rapamycin-Treated Mice¹

Department of Immunology, The Scripps Research Institute, La Jolla, CA 92037

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 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 T cells unable to proliferate, migrate, and produce normal levels of growth factors. The observed impairment of skin T cell function is directly related to the inhibitory action of rapamycin on mammalian target of rapamycin. Skin 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 T cell-produced factor, insulin-like growth factor-1. These studies not only reveal that mammalian target of rapamycin is a master regulator of T cell function but also provide a novel mechanism for the increased susceptibility to nonhealing wounds that occurs during rapamycin administration.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported in part by grants from National Institutes of Health (DK073098 and AI07244) and the Leukemia and Lymphoma Society. This is manuscript number 19281.

² Address correspondence and reprint requests Dr. Julie M. Jameson, Department of Immunology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037. E-mail address: jamesonj{at}scripps.edu

³ Abbreviations used in this: IEL, intraepithelial lymphocyte; IGF-1, insulin-like growth factor-1; KGF-1, keratinocyte growth factor-1; mTOR, mammalian target of rapamycin; mTORC, mTOR complex.