T follicular helper and memory cell responses and the mTOR pathway in murine heart transplantation
Published on Feb 1, 2020in Journal of Heart and Lung Transplantation8.578
· DOI :10.1016/j.healun.2019.11.017
ABSTRACT BACKGROUND Mammalian target of rapamycin (mTOR) inhibitors are valuable immunosuppressants in clinical transplantation, but mTOR regulation of allogeneic T cell responses is not fully understood. Here, we investigated the effects of T cell-specific mTOR deletion on allogeneic T cell responses and heart transplant survival. METHODS Wild type C57BL/6, Mtorfl/flCd4-Cre, Stat3fl/flCd4-Cre, and Mtorfl/flStat3fl/flCd4-Cre mice were transplanted with BALB/c heart allografts, with or without BALB/c skin-sensitization. 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 Mtorfl/flCd4-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 donor skin-sensitized Mtorfl/flStat3fl/flCd4-Cre mice, whereas heart allograft survival was prolonged in donor skin-sensitized Mtorfl/flCd4-Cre and Stat3fl/flCd4-Cre mice. CONCLUSIONS mTOR is required for Tfh cell response in murine heart transplantation. T cell-specific deletion of both mTOR and Stat3 abrogates memory response to heart transplants. These findings help us to better understand the molecular mechanisms underlying T cell immunity to transplanted organs.