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

https://doi.org/10.1016/j.healun.2019.11.017Get rights and content

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 CD62LCD44+ 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.

Section snippets

Mice

C57BL/6 (B6), BALB/c, Cd4-Cre, Mtorfl/fl, and Stat3fl/fl mice were purchased from Jackson Laboratory (Bar Harbor, ME). A further description of these mouse strains is listed in Supplementary Table S1 (available online at www.jhltonline.org/). Mtorfl/fl and Stat3fl/fl mice were crossed with Cd4-Cre mice to create Mtorfl/flCd4-Cre, Stat3fl/flCd4-Cre, and Mtorfl/flStat3fl/flCd4-Cre mice. Mice were housed in a specific pathogen-free facility at the Houston Methodist Research Institute in Houston,

The deletion of mTOR in T cells induce long-term heart allograft survival

To determine the role of mTOR in the regulation of T cell responses in transplantation, BALB/c hearts were transplanted into Mtorfl/flCd4-Cre (B6 background) and wild-type (WT) B6 mice. As shown in Figure 1A, none of the Mtorfl/flCd4-Cre mice rejected their BALB/c heart allografts (median survival time [MST] of > 100 days; n = 5), whereas WT B6 mice rejected BALB/c hearts acutely (MST = 8.6 ± 0.55 days; n = 5). The histology of heart allografts harvested from the Mtorfl/flCd4-Cre recipients at

Discussion

The molecular mechanisms underlying allogeneic T cell responses have not been adequately explored. This study found that all heart allografts survived more than 100 days in mice when mTOR was deleted in T cells. Further mechanistic investigation revealed that mTOR in T cells promoted the expansion of CD4+ and CD8+ effector cells. In addition, mTOR was required for the generation of Tfh and GC B cells in response to heart transplantation. Moreover, in skin-sensitized recipients, although mTOR

Disclosure statement

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.

References (33)

  • H Kopf et al.

    Rapamycin inhibits differentiation of Th17 cells and promotes generation of FoxP3+ T regulatory cells

    Int Immunopharmacol

    (2007)
  • MV Kim et al.

    The transcription factor Foxo1 controls central-memory CD8+ T cell responses to infection

    Immunity

    (2013)
  • W Cui et al.

    An interleukin-21-interleukin-10-STAT3 pathway is critical for functional maturation of memory CD8+ T cells

    Immunity

    (2011)
  • NR Krieger et al.

    CD4+ but not CD8+ cells are essential for allorejection

    J Exp Med

    (1996)
  • EM Bolton et al.

    Cellular requirements for renal allograft rejection in the athymic nude rat

    J Exp Med

    (1989)
  • Z Liu et al.

    CD4(+) T-cell subsets in transplantation

    Immunol Rev

    (2013)
  • View full text