An Interaction between Kynurenine and the Aryl Hydrocarbon Receptor Can Generate Regulatory T Cells

Mezrich, Joshua D.; Fechner, John H.; Zhang, Xiaoji; Johnson, Brian P.; Burlingham, William J.; Bradfield, Christopher A.

doi:10.4049/jimmunol.0903670

Cited by 1,290 publications

(1,231 citation statements)

References 59 publications

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“…Trp degradation is thought to suppress immune cells in two ways: Trp catabolites promote the differentiation of regulatory T cells (Treg) 6–8 and induce apoptosis of T cells 9 . On the other hand, Trp depletion has been implicated in the proliferation arrest of CD8 + T cells 10 by the accumulation of uncharged transfer RNA (tRNA) and subsequent activation of the general control non-derepressible-2 (GCN2) kinase pathway 11,12 , while Gcn2 in T cells has recently been shown to be dispensable for the suppression of antitumor immune responses in experimental melanomas 13 .…”

Section: Introductionmentioning

confidence: 99%

Upregulation of tryptophanyl-tRNA synthethase adapts human cancer cells to nutritional stress caused by tryptophan degradation

et al. 2018

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Tryptophan (Trp) metabolism is an important target in immuno-oncology as it represents a powerful immunosuppressive mechanism hijacked by tumors for protection against immune destruction. However, it remains unclear how tumor cells can proliferate while degrading the essential amino acid Trp. Trp is incorporated into proteins after it is attached to its tRNA by tryptophanyl-tRNA synthestases. As the tryptophanyl-tRNA synthestases compete for Trp with the Trp-catabolizing enzymes, the balance between these enzymes will determine whether Trp is used for protein synthesis or is degraded. In human cancers expression of the Trp-degrading enzymes indoleamine-2,3-dioxygenase-1 (IDO1) and tryptophan-2,3-dioxygenase (TDO2) was positively associated with the expression of the tryptophanyl-tRNA synthestase WARS. One mechanism underlying the association between IDO1 and WARS identified in this study is their joint induction by IFNγ released from tumor-infiltrating T cells. Moreover, we show here that IDO1- and TDO2-mediated Trp deprivation upregulates WARS expression by activating the general control non-derepressible-2 (GCN2) kinase, leading to phosphorylation of the eukaryotic translation initiation factor 2α (eIF2α) and induction of activating transcription factor 4 (ATF4). Trp deprivation induced cytoplasmic WARS expression but did not increase nuclear or extracellular WARS levels. GCN2 protected the cells against the effects of Trp starvation and enabled them to quickly make use of Trp for proliferation once it was replenished. Computational modeling of Trp metabolism revealed that Trp deficiency shifted Trp flux towards WARS and protein synthesis. Our data therefore suggest that the upregulation of WARS via IFNγ and/or GCN2-peIF2α-ATF4 signaling protects Trp-degrading cancer cells from excessive intracellular Trp depletion.

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Section: Introductionmentioning

confidence: 99%

Upregulation of tryptophanyl-tRNA synthethase adapts human cancer cells to nutritional stress caused by tryptophan degradation

et al. 2018

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“…Mice with a poor-affinity AHR suffer from exacerbated autoimmune encephalomyelitis in the absence of an exogenous ligand 26 , and Trp catabolites suppress autoimmune neuroinflammation 29,30 , suggesting that activation of Trp catabolism represents an endogenous feedback loop to restrict inflammation through the AHR. In fact, exogenous Kyn is involved in the regulation of immune cells in mice through the AHR 31,32 . Kyn concentrations sufficient to activate the AHR are also generated by IDO in response to inflammatory stimuli (Supplementary Fig.…”

Section: Article Researchmentioning

confidence: 99%

An endogenous tumour-promoting ligand of the human aryl hydrocarbon receptor

Opitz

Litzenburger

Sahm

et al. 2011

Nature

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“…Several physiological AhR ligands have also been identified, many of them are derivatives of tryptophan. One of those tryptophan-derived AhR ligands is L-kynurenine (L-Kyn) synthesized by 2,3-dioxygenase (IDO) or 2,3-dioxygenase (TDO) [2,3]. Interestingly, IDO has a strong relationship with AhR: not only does IDO synthesize the AhR ligand L-Kyn, but also the expression of IDO is controlled by AhR signaling [4], thus providing a positive feedback loop for AhR activation.…”

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confidence: 99%