TY - JOUR
T1 - T follicular helper and memory cell responses and the mTOR pathway in murine heart transplantation
AU - Xie, Aini
AU - Yan, Hui
AU - Fu, Jinfei
AU - He, Adam
AU - Xiao, Xiang
AU - Li, Xian C.
AU - Chen, Wenhao
N1 - Funding Information:
This study was supported by the startup fund from Houston Methodist Research Institute (to W.C.) and the US National Institutes of Health grant (#NIH R01AI132492 to W.C.). The authors would like to thank the Flow Cytometry Core at Houston Methodist for excellent services.
Funding Information:
The authors have no conflicts of interest to disclose. This study was supported by the startup fund from Houston Methodist Research Institute (to W.C.) and the US National Institutes of Health grant (#NIH R01AI132492 to W.C.). The authors would like to thank the Flow Cytometry Core at Houston Methodist for excellent services.
Publisher Copyright:
© 2019 International Society for Heart and Lung Transplantation
PY - 2020/2
Y1 - 2020/2
N2 - 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, Mtorfl/flCd4-Cre, Stat3fl/flCd4-Cre, and Mtorfl/flStat3fl/flCd4-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 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 the donor skin-sensitized Mtorfl/flStat3fl/flCd4-Cre mice, whereas the heart allograft survival was prolonged in the 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 the memory response to heart transplants. These findings help us to better understand the molecular mechanisms underlying the T cell immunity to transplanted organs.
AB - 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, Mtorfl/flCd4-Cre, Stat3fl/flCd4-Cre, and Mtorfl/flStat3fl/flCd4-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 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 the donor skin-sensitized Mtorfl/flStat3fl/flCd4-Cre mice, whereas the heart allograft survival was prolonged in the 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 the memory response to heart transplants. These findings help us to better understand the molecular mechanisms underlying the T cell immunity to transplanted organs.
KW - T follicular helper
KW - allograft survival
KW - effector T cell
KW - heart transplantation
KW - mTOR
KW - memory T cell response
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U2 - 10.1016/j.healun.2019.11.017
DO - 10.1016/j.healun.2019.11.017
M3 - Article
C2 - 31831210
AN - SCOPUS:85076251518
SN - 1053-2498
VL - 39
SP - 134
EP - 144
JO - Journal of Heart and Lung Transplantation
JF - Journal of Heart and Lung Transplantation
IS - 2
ER -