Wound repair mediated by γδ T cells requires mTOR (87.43)

Abstract

Abstract γδ TCR-expressing lymphocytes in the skin play roles in biological processes such as wound repair, tissue homeostasis, and tumor rejection. γδ T cells regulate their epithelial neighbors by producing growth factors for keratinocyte proliferation, epithelial homeostasis, and inflammatory cell migration. Rapamycin is a triene macrolide, which inhibits mTOR signaling by binding FKBP12, thus inhibiting αβ T lymphocyte function. Rapamycin is approved by the U.S. Food and Drug Administration for the prophylaxis of acute kidney rejection, however patients that receive rapamycin 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. mTOR plays key roles in growth factor and cytokine signal reception, therefore rapamycin administration may mimic nutrient insufficiency. Our preliminary studies indicate that rapamycin arrests skin γδ T cell proliferation in G1 phase and causes them to undergo autophagy. We have established skin organ cultures to administer rapamycin to wounded murine skin. Our results demonstrate that when rapamycin is present, there is a defect in wound closure over time. We propose that rapamycin blocks skin γδ T cells from receiving survival signals, which results in the inhibition of skin γδ T cell proliferation and function negatively impacting wound repair. Support from Leukemia and Lymphoma Society and NIH DK073098.