Infectious tolerance via the consumption of essential amino acids and mTOR signaling

Cobbold, Stephen; Adams, Elizabeth; Farquhar, Claire A.; Nolan, Kathleen F.; Howie, Duncan; Lui, Kathy O.; Fairchild, Paul J.; Mellor, Andrew L.; Ron, David; Waldmann, Herman

doi:10.1073/pnas.0903919106

Cited by 285 publications

(307 citation statements)

References 43 publications

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“…The magnitude of the Treg conversion-enhancing effect by inhibitors of the PI3K/Akt/mTOR pathway became even more obvious under conditions of strong costimulation (ratio 1:5), supporting the concept that Foxp3 induction can be increased by enhanced costimulatory signals in the presence of PI3K/Akt/mTOR inhibition (14), whereas CD28 signals have been shown to interfere with Treg conversion in the presence of TGFβ only. Synergism between TGFβ and mTOR inhibitors has been demonstrated (14,26); however, blockade of the TGFβ signaling pathway did not interfere with Foxp3 induction Fig. 3.…”

Section: Resultsmentioning

confidence: 89%

Enhancement of antigen-specific Treg vaccination in vivo

Daniel

Wennhold²,

Kim³

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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The conversion of naive T cells into Treg can be achieved in vivo by delivery of antigen under subimmunogenic conditions. Here we have examined several drugs for their ability to enhance the conversion process in vivo and have found that the rapamycin analog everolimus potently enhances Treg conversion by interfering with T-cell costimulation, reducing cell division and thereby activation of DNA methyltransferase 1 as well as by reducing T-cell activation through the ATP-gated P2×7 receptor controlling Ca2 + influx. The resulting Tregs exhibit increased stability of Foxp3 expression even when generated in TGFβ-containing media in vitro. Thus the mammalian target of rapamycin (mTOR) inhibitor everolimus in addition to inhibiting immune responses enhances Treg conversion by several distinct pathways. The converted Tregs can be further expanded by injection of IL-2/IL-2ab complexes. These complexes also increase the number of CD25 + Foxp3 − cells that, however, do not represent cytokine secreting effector cells but anergic cells, some of which can secrete IL-10 and can themselves be considered regulatory T cells as well. The combined use of everolimus and IL-2/IL-2ab complexes in vivo makes it feasible to achieve highly effective antigen-driven conversion of naive T cells into Treg and their expansion in vivo and thereby the described protocols constitute important tools to achieve immunological tolerance by Treg vaccination.antigen-specific Treg conversion | Foxp3 | IL-2/IL-2ab complexes | mammalian target of rapamycin | prospective tolerance A t present it is unclear how much the conversion of naive T cells into Treg in peripheral lymphoid tissue contributes to the control of immunity by Treg. On the other hand, it seems reasonable to exploit this conversion process to control unwanted immune responses. In the past our lab has described several strategies to induce such conversion by exogenous antigens with the aim to study whether Treg conversion can be used to induce tolerance to antigens, including transplantation antigens, prospectively (1-3). We were successful in using this approach to induce prospective tolerance in female mice to a variety of male tissues, including skin and hematopoetic grafts (4).With regard to mechanisms it became clear that Treg conversion in vivo is best achieved by subimmunogenic delivery of strong agonists under conditions that avoid functional activation of antigen presenting cells (5-9). Also, in accordance with more recent data (10), in this setting, best conversion is seen in T cells that undergo only limited proliferation, whereas higher doses of the strong agonist result in more extensive proliferation and diminished conversion (5). Thus these studies that addressed Treg conversion by monitoring the generation of Foxp3-expressing Treg in vivo confirmed anecdotal evidence of generating "dominant" tolerance by subimmunogenic antigen delivery (10).Comparison of such converted Treg with Treg generated by T-cell stimulation in vitro in the presence of relatively high doses of tran...

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Section: Resultsmentioning

confidence: 89%

Enhancement of antigen-specific Treg vaccination in vivo

Daniel

Wennhold²,

Kim³

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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“…There is accumulating evidence that Leu and Leu cellular import are involved in T cell activation (21)(22)(23). Sinclair et al (22) showed that the System L transporter, Slc7a5, is a key factor in T cell metabolic reprogramming that directs Leu transport and controls mTORC1 activity (22).…”

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confidence: 99%

“…Moreover, the Leu antagonist N-acetyl-leucine amide (NALA) inhibits mTORC1 activity and T cell function (23). Similarity, essential amino acid depletion inhibits mTOR and promotes infectious tolerance via generation of regulatory T cells (21).…”

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confidence: 99%

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Cytosolic Branched Chain Aminotransferase (BCATc) Regulates mTORC1 Signaling and Glycolytic Metabolism in CD4+ T Cells

Ananieva

Patel

Drake

et al. 2014

Journal of Biological Chemistry

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Background: Cytosolic branched chain aminotransferase (BCATc) initiates Leu catabolism. In T cells, Leu activates mTORC1, the role of BCATc is unknown. Results: BCATc stimulates Leu transamination, whereas loss of BCATc expression increases Leu concentrations, mTORC1 signaling, and glycolysis in T cells. Conclusion: BCATc is a novel immunosuppressive enzyme controlling Leu supply for mTORC1 in T cells. Significance: A new link is revealed between amino acid metabolism and the immune response.

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“…We did, however, notice a general trend for LPS-induced expression of various amino-acid catabolic enzymes, which could represent components of a redundant mechanism for mediating tolerance through depletion of essential amino acids [27]. The modulated BMDC populations were clearly not refractory to LPS stimulation, but instead retained much of the normal LPSinduced transcription response.…”

Section: Discussionmentioning

confidence: 68%

Tolerogenicity is not an absolute property of a dendritic cell

et al. 2010

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Pharmacological modulation is known to temper the immune capacity of DC, enhancing the notion that modulated Ag-bearing DC might be used therapeutically to induce tolerance. We have investigated phenotypic features shared by such DC, and queried their potential to tolerize in different settings. Immature, IL-10, TGF-b and 1a,25-dihydroxyvitamin D 3 -modulated BMDC all induced tolerance to male skin in female TCR transgenic A1.RAG mice, and the modulated DC also tolerized after exposure to the TLR4-ligand LPS. Transcript profiling revealed that this was achieved despite retaining much of the normal LPS-maturation response. No shared tolerance-associated transcripts could be identified. Equivalent BMDC could not tolerize in Marilyn TCR-transgenic mice. Simultaneous presentation of both A1.RAG and Marilyn peptide-Ag (Dby-H2E k and Dby-H2A b ) on immature (C57BL/6JxCBA/Ca) F1 BMDC also only achieved tolerance in A1.RAG mice. Both strains registered Ag, but Foxp3 1 Treg were only induced in A1.RAG mice. In contrast, Marilyn T cells showed greater proliferation and an inflammatory bias, in response to Ag presented by immature F1 BMDC in vitro. In summary, while pharmacological agents can skew DC to reinforce their immature tolerogenic phenotype, the outcome of presentation is ultimately an integrated response including T-cell-intrinsic components that can over-ride for immune activation.Key words: DC . TCR transgenic mice . Transplantation tolerance Supporting Information available online IntroductionDespite enthusiasm to exploit tolerogenic DC clinically [1][2][3], what constitutes a tolerogenic DC in vivo, and how it achieves tolerance, is still poorly understood. Immunological outcome was thought to be related directly to the maturation status of DC, with immature DC presenting for tolerance [4][5][6]; however, this simple view rapidly failed to account for accumulating experimental observations [7,8]. The functional diversity of DC has more recently been explained by the integration of multiple factors within a particular anatomical location causing the differentiation of appropriately tuned ''effector'' DC [9,10]. Although key co-inhibitory receptors, such as ILT3/4, PIR-B, PD-L1 and ICOSL, and immunoregulatory molecules, such as IDO and histone deacetylase HDAC11, have been variously implicated in driving tolerance [11][12][13][14][15][16], it is still not clear to what degree such molecules are universal players.A concern using immature DC in vivo is that they might become activated, particularly within the context of inflammation. If DC are to be used therapeutically, then the tolerant phenotype must be robust and stable. Numerous agents have been used to manipulate Ã These authors contributed equally to this study.ÃÃ These authors contributed equally to this study as senior authors. 1728DC in vitro to generate maturation-resistant cells for adoptive cell therapy [2,9]; however, attempts to induce tolerance to allografts in conventional models have generally failed unless combined with other immunosuppressive...

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Infectious tolerance via the consumption of essential amino acids and mTOR signaling

Cited by 285 publications

References 43 publications

Enhancement of antigen-specific Treg vaccination in vivo

Enhancement of antigen-specific Treg vaccination in vivo

Cytosolic Branched Chain Aminotransferase (BCATc) Regulates mTORC1 Signaling and Glycolytic Metabolism in CD4+ T Cells

Tolerogenicity is not an absolute property of a dendritic cell

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