Rapamycin impairs skin γδ T cell function resulting in autophagy

Abstract

Epithelial tissues provide barrier functions vital to the survival of the organism. To maintain this protective role, there is a complex regulation of epithelial cell proliferation and survival. γδ TCR‐expressing lymphocytes reside within the epithelia where they regulate tissue homeostasis and repair by producing growth factors, cytokines, and chemokines. Chronic nonhealing wounds are a devastating consequence of defective tissue repair. Patients that receive the immunosuppressant Rapamycin for the prophylaxis of acute kidney rejection report an increased incidence of wound healing complications. We hypothesize that rapamycin not only targets allograft‐specific αβ T lymphocytes, but also suppresses skin γδ T cells resulting in defective tissue repair. Rapamycin inhibits the signaling molecule mTOR, a key player in growth factor and cytokine signal reception. We have established a murine model of rapamycin administration in which there is delayed wound repair. Treatment with rapamycin arrests skin γδ T cell proliferation in G1 phase and causes the T cells to undergo autophagy. In addition skin γδ T cells exhibit a defect in TNF‐α production at the wound site. We propose that rapamycin blocks the ability of skin γδ T cells to receive nutrient and growth factor signals resulting in autophagy. This limits the ability of skin γδ T cells to proliferate and negatively impacts their ability to mediate wound repair.Support from Leukemia and Lymphoma Society and NIH DK073098.