The Combined Effects of Tryptophan Starvation and Tryptophan Catabolites Down-Regulate T Cell Receptor ζ-Chain and Induce a Regulatory Phenotype in Naive T Cells

Fallarino, Francesca; Grohmann, Ursula; You, Sylvaine; McGrath, Barbara C.; Cavener, Douglas R.; Vacca, Carmine; Orabona, Ciriana; Bianchi, Roberta; Belladonna, Maria Laura; Volpi, Claudia; Santamaría, Pere; Fioretti, Maria Cristina; Puccetti, Paolo

doi:10.4049/jimmunol.176.11.6752

Cited by 939 publications

(854 citation statements)

References 58 publications

(90 reference statements)

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“…The activation of these cell types is, to different extents and via different mechanisms, modulated by tryptophan catabolism, which may eventually lead to the generation of CTLA-4-expressing Treg cells [12]. This suggests another potential biological relevance of the mutual regulation of IDO and IFN-a in CD19 + DC i.e., as a clue to the coordinate balance of Treg suppression and inflammation respectively.…”

Section: How Ido Regulates Type I/ii Ifnmentioning

confidence: 99%

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On watching the watchers: IDO and type I/II IFN

Puccetti

2007

Eur J Immunol

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A series of recent studies, including an article in this issue of the European Journal of Immunology, have demonstrated that the immunoregulatory pathway of tryptophan catabolism, initiated by the enzyme indoleamine 2,3-dioxygenase (IDO), not only represents an effector mechanism of peripheral tolerance, but is also a critical participant in the promotion of an optimally protective immune response balanced between inflammation and tolerance. Although subjected to transcriptional regulation by type I/II IFN, IDO is itself required for the production of type I IFN in response to B7 signaling in CD19 + DC. Such a bidirectional feedback loop could be part of an integrated response for preventing excessive inflammation and autoimmunity.

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Section: How Ido Regulates Type I/ii Ifnmentioning

confidence: 99%

“…Because IDO contributes to the peripheral generation of Treg cells [12], not only may CTLA-4 + Treg cells expand their own population through pDC, but the pDC themselves could exploit TLR-dependent and -independent mechanisms to activate IDO and exert a regulatory control over an excessively inflammatory milieu dominated by IFN production [13].…”

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confidence: 99%

On watching the watchers: IDO and type I/II IFN

Puccetti

2007

Eur J Immunol

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“…In addition, it has been shown that kynurenines were able to abrogate the Th17-promoting capacity of IL-23 in Th17 cells (12). In addition, Fallarino et al have also shown that in a long-term cell culture (7 days), low tryptophan concentration (35 lM), and an equimolar mixture of kynurenine, AA, 3-HK, 3-HAA, and QA promote conversion of naive CD4 1 T cells into CD25 1 Foxp3 1 regulatory T cells (Treg) (40). Here, it is shown that in iLN from mice with established CIA the mean concentration of tryptophan was in a similar micro molar (lM) range as previously applied by Fallarino et al (40).…”

Section: Discussionmentioning

confidence: 99%

“…In addition, Fallarino et al have also shown that in a long-term cell culture (7 days), low tryptophan concentration (35 lM), and an equimolar mixture of kynurenine, AA, 3-HK, 3-HAA, and QA promote conversion of naive CD4 1 T cells into CD25 1 Foxp3 1 regulatory T cells (Treg) (40). Here, it is shown that in iLN from mice with established CIA the mean concentration of tryptophan was in a similar micro molar (lM) range as previously applied by Fallarino et al (40). However, it is difficult to extrapolate data showing values of IC 50 for small molecules tested in vitro with biological effects in vivo.…”

Section: Discussionmentioning

confidence: 99%

An exploratory study of the interplay between decreased concentration of tryptophan, accumulation of kynurenines, and inflammatory arthritis

Kolodziej

2012

IUBMB Life

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Tryptophan is an essential amino acid which influences a wide range of physiological processes, including mood, cognition, and immunity. In the autoimmune diseases, such as rheumatoid arthritis (RA), the induction of tryptophan catabolism may help to diminish exacerbated immune responses. In this study, using collagen‐induced arthritis (CIA) in DBA/1 mice which is an animal model of RA, the endogenous activity of the kynurenine pathway in the immune system was monitored before and after onset of the disease. An increased rate of the initiation of tryptophan catabolism via the kynurenine pathway throughout CIA has been observed. However, decreased tryptophan concentration in the lymph nodes from pre‐arthritic mice was not enough to prevent development of CIA. In contrast, resolution of inflammation coincided with the decreased concentration of tryptophan and accumulation of its catabolites: kynurenine, anthranilic acid, and 3‐hydroxyanthranilic acid in lymph nodes but not in the spleen. In addition, the lack of the accumulation of kynurenine and its downstream metabolites in the pre‐arthritic lymph nodes coincided with increased mRNA expression for genes involved in the catabolism of kynurenine (Kynureninase, kynurenine 3‐monooxygenase, and 3‐hydroxyanthranilate 3,4 dioxygenase). However, in the lymph nodes from mice with established CIA, mRNA expression for these genes was normalized. Hence, keeping in mind an exploratory character of the results, it can be postulated that an anti‐inflammatory role of the kynurenine pathway reaches its full potential only when decreased concentration of tryptophan coincides with accumulation of kynurenines driven by metabolic regulation of gene expression on the kynurenine pathway. © 2012 IUBMB IUBMB Life, 64(12): 983–987, 2012

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“…The third enzyme that catabolises Trp, tryptophan 2,3‐dioxygenase, is expressed mainly in the liver. Increased IDO expression associates with tolerogenic pathways because of Trp depletion and has been associated with the formation of tolerogenic dendritic cells and induction of T regulatory (T reg ) cells 6, 7. Kynurenines are Trp metabolites that stimulate aryl hydrocarbon receptors and associated downstream immunoregulatory pathways 8, 9…”

Section: Introductionmentioning

confidence: 99%

Tryptophan and arginine catabolic enzymes and regulatory cytokines in clinically isolated syndrome and multiple sclerosis

et al. 2018

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ObjectivesClinically isolated syndrome (CIS) is the earliest clinical episode in multiple sclerosis (MS). A study of circulating cells from patients with CIS may help us understand the transition to, and processes associated with, the development of MS.MethodsAs immune cell activity can be determined by flux through metabolic pathways, the mRNA expression of l‐tryptophan‐ and l‐arginine‐catabolising enzymes, indoleamine 2,3‐dioxygenase (IDO) 1 and IDO2 and arginase (ARG) 1 and ARG2, respectively, was compared between peripheral blood mononuclear cells (PBMCs) from healthy controls, and patients with CIS and definite MS. As one measure of cell function, cytokine mRNA levels were analysed directly ex vivo and in cells after culture for 4 h in the absence of regulatory factors in autologous serum.ResultsWhen measured directly ex vivo, the expression of IDO and ARG was greater in cells from patients with CIS and MS than cells from healthy controls. Although not linked to IDO and ARG expression, PBMCs from the CIS patients were characterised by low IL‐10 and TGFB mRNA levels and not by greater expression of proinflammatory cytokines. When the cells were cultured for 4 h without autologous serum, pro‐ and anti‐inflammatory cytokine mRNA levels positively correlated with IDO1 expression, and TGFB mRNA levels correlated with ARG1 expression.ConclusionHigher IDO and ARG expression in CIS and MS provides one sustained homeostatic mechanism to control MS‐associated inflammation. However, potent extrinsic mediators in serum may regulate immune cell function in CIS and associations between IDO, ARG and cytokine expression.

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The Combined Effects of Tryptophan Starvation and Tryptophan Catabolites Down-Regulate T Cell Receptor ζ-Chain and Induce a Regulatory Phenotype in Naive T Cells

Cited by 939 publications

References 58 publications

On watching the watchers: IDO and type I/II IFN

On watching the watchers: IDO and type I/II IFN

An exploratory study of the interplay between decreased concentration of tryptophan, accumulation of kynurenines, and inflammatory arthritis

Tryptophan and arginine catabolic enzymes and regulatory cytokines in clinically isolated syndrome and multiple sclerosis

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