BACKGROUND: The mammalian target of rapamycin (mTOR) inhibitors are valuable immunosuppressants in clinical transplantation; however, the mTOR regulation of allogeneic T-cell responses is not fully understood yet. Therefore, the objective of this study is to investigate the effects of T-cell-specific mTOR deletion on the allogeneic T-cell responses and heart transplant survival. METHODS: BALB/c heart allografts, with or without BALB/c skin sensitization, were transplanted in the wild-type C57BL/6, Mtor(fl/fl) Cd4-Cre, Stat3(fl/fl) Cd4-Cre, and Mtor(fl/fl) Stat3(fl/fl) Cd4-Cre mice. Graft survival and histology, as well as T-cell frequencies and phenotypes, were evaluated after transplantation. RESULTS: In the absence of donor skin sensitization, long-term heart allograft survival was achieved in the Mtor(fl/fl) Cd4-Cre recipients, which was associated with significantly decreased frequencies of CD62L(-)CD44(+) effector T cells and BCL-6(+)CXCR5(+) T follicular helper (Tfh) cells in the periphery. Long-term heart allograft survival was also achieved in the donor skin-sensitized Mtor(fl/fl) Stat3(fl/fl) Cd4-Cre mice, whereas the heart allograft survival was prolonged in the donor skin-sensitized Mtor(fl/fl) Cd4-Cre and Stat3(fl/fl) Cd4-Cre mice. CONCLUSIONS: mTOR is required for Tfh cell response in murine heart transplantation. T-cell-specific deletion of both mTOR and Stat3 abrogates the memory response to heart transplants. These findings help us to better understand the molecular mechanisms underlying the T cell immunity to transplanted organs. (C) 2019 International Society for Heart and Lung Transplantation. All rights reserved.