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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
Aini Xie (HUST: Huazhong University of Science and Technology), Hui Yan1
Estimated H-index: 1
(Houston Methodist Hospital)
+ 4 AuthorsWenhao Chen3
Estimated H-index: 3
(Cornell University)
Abstract
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.
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CD4+ T cells orchestrate immune responses and destruction of allogeneic organ transplants, but how this process is regulated on a transcriptional level remains unclear. Here, we demonstrated that interferon regulatory factor 4 (IRF4) was a key transcriptional determinant controlling T cell responses during transplantation. IRF4 deletion in mice resulted in progressive establishment of CD4+ T cell dysfunction and long-term allograft survival. Mechanistically, IRF4 repressed PD-1, Helios, and othe...
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Summary The differentiation of CD4 + helper T cell subsets with diverse effector functions is accompanied by changes in metabolism required to meet their bioenergetic demands. We find that follicular B helper T (Tfh) cells exhibited less proliferation, glycolysis, and mitochondrial respiration, accompanied by reduced mTOR kinase activity compared to T helper 1 (Th1) cells in response to acute viral infection. IL-2-mediated activation of the Akt kinase and mTORc1 signaling was both necessary and ...
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