Dataset Information

T follicular helper and memory cell responses and the mTOR pathway in murine heart transplantation.

ABSTRACT:

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/flCd4-Cre, Stat3^fl/flCd4-Cre, and Mtor^fl/flStat3^fl/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 Mtor^fl/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 Mtor^fl/flStat3^fl/flCd4-Cre mice, whereas the heart allograft survival was prolonged in the donor skin-sensitized Mtor^fl/flCd4-Cre and Stat3^fl/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.

SUBMITTER: Xie A

PROVIDER: S-EPMC6981023 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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Publications

T follicular helper and memory cell responses and the mTOR pathway in murine heart transplantation.

Xie Aini A Yan Hui H Fu Jinfei J He Adam A Xiao Xiang X Li Xian C XC Chen Wenhao W

The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation 20191126 2

<h4>Background</h4>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.<h4>Methods</h4>BALB/c heart allografts, with or without BALB/c skin sensitization, were transplanted in the wil ...[more]

PMID: 31831210

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Project description:Through the interaction of T follicular helper (Tfh) cells and B cells, efficacious vaccines can generate high-affinity, pathogen-neutralizing antibodies, and memory B cells. Using CXCR5, CXCR3, CCR6, CCR7, PD1, and ICOS as markers, Tfh-like cells can be identified in the circulation and be classified into three functionally distinct subsets that are PD1+ICOS+, PD1+ ICOS-, or PD1-ICOS-. We used these markers to identify different subsets of CXCR5+CD4+ Tfh-like cells in response to highly immunogenic and efficacious vaccines for human papillomaviruses (HPV): Cervarix and Gardasil. In this small study, we used PBMC samples from 11 Gardasil recipients, and 8 Cervarix recipients from the Vaccine Research Center 902 Study to examine the induction of circulating Tfh-like cells and IgD-CD38HiCD27+ memory B cells by flow cytometry. PD1+ICOS+ CXCR3+CCR6-CXCR5+CD4+ (Tfh1-like) cells were induced and peaked on Day (D) 7 post-first vaccination, but not as much on D7 post-third vaccination. We also observed a trend toward increase in PD1+ICOS+ CXCR3-CCR6-CXCR5+CD4+ (Tfh2-like) cells for both vaccines, and PD1+ICOS+ CXCR3-CCR6+CXCR5+CD4+ (Tfh17-like) subset was induced by Cervarix post-first vaccination. There were also minimal changes in the other cellular subsets. In addition, Cervarix recipients had more memory B cells post-first vaccination than did Gardasil recipients at D14 and D30. We found frequencies of memory B cells at D30 correlated with anti-HPV16 and 18 antibody titers from D30, and the induction levels of memory B cells at D30 and PD1+ICOS+Tfh1-like cells at D7 post-first vaccination correlated for Cervarix. Our study showed that induction of circulating CXCR5+CD4+ Tfh-like subsets can be detected following immunization with HPV vaccines, and potentially be useful as a marker of immunogenicity of vaccines. However, further investigations should be extended to different cohorts with larger sample size to better understand the functions of these T cells, as well as their relationship with B cells and antibodies.

Dataset Information

T follicular helper and memory cell responses and the mTOR pathway in murine heart transplantation.

Background

Methods

Results

Conclusions

Publications

T follicular helper and memory cell responses and the mTOR pathway in murine heart transplantation.

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