Evolving Perspectives of mTOR Complexes in Immunity and Transplantation

Fantus, Daniel; Thomson, Angus W.

doi:10.1111/ajt.13151

Cited by 41 publications

(36 citation statements)

References 97 publications

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“…These results are apparently in contrast with the widely accepted Treg-promoting effect of RAPA, and highlight the complexities of mTOR inhibition [83]. Short-term exposure to RAPA inhibits mTORC1 complex but enhances the mTORC2 signal, while prolonged exposure to RAPA is necessary to inhibit both signals [84].…”

Section: Discussionmentioning

confidence: 99%

Single and combined effect of retinoic acid and rapamycin modulate the generation, activity and homing potential of induced human regulatory T cells

et al. 2017

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Adoptive transfer of CD4+CD25+FOXP3+ regulatory T cells (Treg cells) has been successfully utilized to treat graft versus host disease and represents a promising strategy for the treatment of autoimmune diseases and transplant rejection. The aim of this study was to evaluate the effects of all-trans retinoic acid (atRA) and rapamycin (RAPA) on the number, phenotype, homing markers expression, DNA methylation, and function of induced human Treg cells in short-term cultures. Naive T cells were polyclonally stimulated and cultured for five days in the presence of different combinations of IL-2, TGF-β1, atRA and RAPA. The resulting cells were characterized by the expression of FOXP3, activation, surface and homing markers. Methylation of the Conserved Non-coding Sequence 2 was also evaluated. Functional comparison of the different culture conditions was performed by suppression assays in vitro. Culturing naive human T cells with IL-2/TGFβ1 resulted in the generation of 54.2% of Treg cells (CD4+CD25+FOXP3+) whereas the addition of 100 nM atRA increased the yield of Treg cells to 66% (p = 0.0088). The addition of RAPA did not increase the number of Treg cells in any of these settings. Treg cells generated in the presence of atRA had an increased expression of the β7 integrin to nearly 100% of the generated Treg cells, while RAPA treated cells showed enhanced expression of CXCR4. The differential expression of homing molecules highlights the possibility of inducing Treg cells with differential organ-specific homing properties. Neither atRA nor RAPA had an effect on the highly methylated CNS2 sites, supporting reports that their contribution to the lineage stability of Treg cells is not mediated by methylation changes in this locus. Treg cells generated in the presence of RAPA show the most potent suppression effect on the proliferation of effector cells.

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Section: Discussionmentioning

confidence: 99%

Single and combined effect of retinoic acid and rapamycin modulate the generation, activity and homing potential of induced human regulatory T cells

et al. 2017

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“…8 Thus, genetic deletion of either mTORC1 or mTORC2 in T cells has revealed that T helper (Th) 1 and Th17 differentiation is selectively regulated by mTORC1, whereas Th2 development is mTORC2-dependent. 9,10 Furthermore, inhibition of both mTORC1 and mTORC2 favors regulatory T cell (Treg) development more than inhibition of either complex alone.…”

Section: Introductionmentioning

confidence: 99%

Influence of the Novel ATP-Competitive Dual mTORC1/2 Inhibitor AZD2014 on Immune Cell Populations and Heart Allograft Rejection

et al. 2017

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Background Little is known about how new generation adenosine triphosphate (ATP)-competitive mechanistic target of rapamycin (mTOR) kinase inhibitors (TORKinibs) affect immunity and allograft rejection. Methods mTOR complex (C) 1 and 2 signaling in dendritic cells (DC) and T cells was analyzed by Western blotting, while immune cell populations in normal and heart allograft recipient mice were analyzed by flow cytometry. Alloreactive T cell proliferation was quantified in MLR; intracellular cytokine production and serum antidonor IgG levels were determined by flow analysis and immunofluorescence staining used to detect IgG in allografts. Results The novel TORKinib AZD2014 impaired DC differentiation and T cell proliferation in vitro and depressed immune cells and allospecific T cell responses in vivo. A 9-day course of AZD2014 (10 mg/kg ip twice daily) or rapamycin (RAPA; 1mg/kg ip daily) prolonged median heart allograft survival time significantly (25 days for AZD2014; 100 days for RAPA; 9.5 days for control). Like RAPA, AZD2014 suppressed graft mononuclear cell infiltration, increased regulatory T cell (Treg) to effector memory T cell (Tem) ratios and reduced T follicular helper (Tfh) and B cells 7 days posttransplant. By 21 days (10 days after drug withdrawal), however, Tfh and B cells and donor-specific IgG1 and IgG2c antibody titers were significantly lower in RAPA- compared with AZD2014-treated mice. Elevated Treg to Tem ratios were maintained after RAPA, but not AZD2014 withdrawal. Conclusions Immunomodulatory effects of AZD2014, unlike those of RAPA, were not sustained after drug withdrawal, possibly reflecting distinct pharmacokinetics or/and inhibitory effects of AZD2014 on mTORC2.

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“…Als mTOR-Hemmer (mTOR: "mechanistic [or mammalian] target of rapamycin") wird eine Gruppe von Substanzen beschrieben, die die mTOR-Signalwege (mTORC1 und mTORC2) unterbrechen [64]. Bekannte Vertreter sind beispielsweise Sirolimus und Everolimus, die u. a. zur Immunsuppression z.…”

Section: Mtor-hemmerunclassified

“…Bekannte Vertreter sind beispielsweise Sirolimus und Everolimus, die u. a. zur Immunsuppression z. B. bei Transplantatempfängern eingesetzt werden [64].…”

Section: Mtor-hemmerunclassified