Tryptophan Deprivation Induces Inhibitory Receptors ILT3 and ILT4 on Dendritic Cells Favoring the Induction of Human CD4+CD25+ Foxp3+ T Regulatory Cells

Brenk, Manuela; Scheler, Marina; Koch, Susanne; Neumann, Jürgen; Takikawa, Osamu; Häcker, Georg; Bieber, Thomas; Bubnoff, Dagmar von

doi:10.4049/jimmunol.0803277

Cited by 145 publications

(128 citation statements)

References 56 publications

Supporting

Mentioning

120

Contrasting

Unclassified

Order By: Relevance

“…Tryptophan degradation and kynurenine generation are associated with T cell hyporesponsiveness and apoptosis. Additionally, under certain circumstances, tryptophan metabolism has been shown to induce a positive feedback loop augmenting FoxP3-expressing Treg cells (35,36). IDO is upregulated by proinflammatory cytokines in an attempt to modulate immune responsiveness and therefore represents a natural negative regulatory pathway.…”

Section: Discussionmentioning

confidence: 99%

Regulation of myeloperoxidase‐specific T cell responses during disease remission in antineutrophil cytoplasmic antibody–associated vasculitis: The role of Treg cells and tryptophan degradation

Chavele¹,

Shukla²,

Keteepe-Arachi³

et al. 2010

Arthritis & Rheumatism

View full text Add to dashboard Cite

Objective. T lymphocytes have been implicated in the pathogenesis of antineutrophil cytoplasmic antibody-associated vasculitis (AAV). Patients with myeloperoxidase (MPO)antineutrophil cytoplasmic antibody (ANCA) experience relapses less frequently than those with proteinase 3 ANCA, suggesting greater immune regulation. This study was undertaken to investigate MPO-specific T cell reactivity during disease remission and the factors regulating their responsiveness.Methods. MPO-specific T cells were quantified by enzyme-linked immunospot assay with additional Treg cell depletion or exogenous interleukin-2. Serum tryptophan and its metabolites were measured. In vivo blockade of indoleamine 2,3-dioxygenase (IDO) was performed, and its effect on MPO reactivity was assessed.Results. During disease remission, MPO-specific interferon-␥-producing T cell frequencies were comparable with those found in healthy controls and significantly lower than those found in patients with acute disease. CD4؉CD25؉ regulatory cells did not play a role in maintaining these low MPO-specific T cell frequencies, since depletion of Treg cells did not augment MPO-specific responses, and FoxP3 levels were diminished in patients compared with controls. Treg cell function, however, was comparable in patients and controls, suggesting numerical rather than functional deficiency. We found diminished serum tryptophan levels and elevated levels of its metabolite kynurenine in patients with MPO AAV as compared with controls. To confirm the effect of tryptophan degradation on MPO responses in vivo, we inhibited degradation in MPOimmunized WKY rats and found greater immune responsiveness to MPO and a tendency to more severe glomerulonephritis.Conclusion. Our findings indicate that MPOspecific T cell frequencies are regulated during disease remission in association with tryptophan degradation. The tryptophan regulatory pathway is induced during active disease and persists during disease remission.The antineutrophil cytoplasmic antibodyassociated vasculitides (AAV) are a group of relapsingremitting systemic diseases that result in considerable morbidity and mortality. Up to 25% of patients develop end-stage renal failure despite optimal immunosuppression. Understanding the immune mechanisms that regulate disease activity is critical for a more successful therapeutic approach to management of the disease. Recent work has highlighted the importance of both humoral and cellular effectors in disease pathogenesis. Pathogenic transplacental transfer of antimyeloperoxidase (anti-MPO) antibody to a neonate has been re-

show abstract

Section: Discussionmentioning

confidence: 99%

Regulation of myeloperoxidase‐specific T cell responses during disease remission in antineutrophil cytoplasmic antibody–associated vasculitis: The role of Treg cells and tryptophan degradation

Chavele¹,

Shukla²,

Keteepe-Arachi³

et al. 2010

Arthritis & Rheumatism

View full text Add to dashboard Cite

show abstract

“…MSCs from different sources were shown to induce tolerogenic DCs [12][13][14][15]21], but this is the first time showing what mechanisms operate between MSC-induced tolerogenic DCs and Treg cells. Namely, we found that IDO-1, ILT-3, and ILT-4 expressed by PL-MSC-developed DCs are crucial for the induction of functional Foxp3 + Treg cells, which is already described mechanism utilized by tolerogenic DCs [22,23]. Besides Foxp3, CD39 was recognized recently as a key marker of functional Treg cells [27].…”

mentioning

confidence: 96%

“…To evaluate why PL-MSC-developed DCs possess lower allostimulatory ability and Th2 polarization, in spite of their phenotypical maturation, we studied the expression of coinhibitory molecules (IDO-1, ILT-3, and ILT-4) characteristic for tolerogenic DCs [22,23]. The pro-inflammatory cocktail reduced the expression of IDO-1 and ILT-3, and increased the expression of ILT-4 by control mDCs (Fig.…”

Section: Pl-msc-developed Dcs Induce Anergy and Functional Treg-cell mentioning

confidence: 99%

Mesenchymal stem cells from periapical lesions modulate differentiation and functional properties of monocyte‐derived dendritic cells

et al. 2013

View full text Add to dashboard Cite

Immunoregulatory mechanisms within periapical lesions (PLs) are as of yet unexplored. Considering the crucial role of DCs in controlling the immune response within PLs, the immunomodulatory properties of mesenchymal stem cells (MSCs), and the colocalization of MSCs and DCs in situ, we wondered whether MSCs from PLs modulate the development and functions of DCs. Using a model of monocyte-derived DCs, we showed that PL-MSCs inhibited differentiation of DCs via soluble factors, of which IL-6 had a minor effect, but did not impair their subsequent maturation induced by pro-inflammatory cytokines. However, upon maturation such DCs favored the production of Th2/Th17 cytokines by allogenic CD4 + lymphocytes in coculture, compared with mature DCs differentiated without PL-MSCs. PL-MSC-differentiated DCs, cultivated with pro-inflammatory cytokines and PL-MSCs, although phenotypically mature, exhibited poor allostimulatory activity, induced anergy, Th2 polarization, differentiation of suppressive CD4 + CD25 high CD39 + Treg-cell subsets via IDO-1-, ILT-3-, and ILT-4-dependent mechanisms, and increased production of TGF-β in the coculture. In contrast, DCs cultivated with PL-MSCs only during maturation stimulated proliferation and Th1 polarization of CD4 + T cells in an IL-12-independent manner. In conclusion, PL-MSCs significantly modulate the development and functions of DCs, depending on the phase of DCs development during which the interaction occurs. Keywords: Dendritic cells r Mesenchymal stem cells r Periapical lesions r Th polarizationAdditional supporting information may be found in the online version of this article at the publisher's web-site IntroductionPeriapical lesions (PLs) are a common pathology within the human population initiated by the bacterial invasion of the root canal and develop from an acute inflammatory response to the formation of granulomas or cysts infiltrated by various inflammatory cells [1].Correspondence: Prof. MiodragČolić e-mail: fakultet.vma@mod.gov.rs Furthermore, cytokines produced by Th cells have been shown to play a crucial role in PLs pathogenesis. Namely, Th1-and Th17-derived cytokines promote inflammation, bone resorption, and disease progression. Th2 cells seem to be important for the later phases of PLs development, whereas IL-10 and TGF-β produced by Treg cells seem to be important for the healing processes within PLs [2,3]. However, it is not yet clear which mediators and cells are involved crucially in the regulation of Th-cell commitment during the development, maintenance, and resolution of the disease.C 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu Eur. J. Immunol. 2013. 43: 1862-1872 Immunomodulation 1863DCs are the key regulatory and decision-making cells with a unique ability to activate naive T cells and polarize their development. These cells can be differentiated in vitro from monocytes or CD34 + -progenitors with GM-CSF and IL-4, generating CD1a + CD14 − immature DCs (iDCs) [4]. Alternatively, in the absence of IL-4, GM-CSF induces the differ...

show abstract

“…In differentiating human myeloid DCs, trp deprivation induces the inhibitory receptors immunoglobulin-like transcript 3 (ILT3) and ILT4 and the upregulation of the C/ EBP-homologous protein, which is indicative of GCN2 stress response (33). These 'tolerogenic' DCs have an increased capacity to induce Tregs from CD4 + CD25 -Foxp3 -T cells with suppressive activity.…”

Section: Immune Tolerance Induction Through Trp Starvation and Trp Mementioning

confidence: 99%

The indoleamine 2,3‐dioxygenase (IDO) pathway controls allergy

Bubnoff

Bieber

2012

Allergy

View full text Add to dashboard Cite

A series of recent studies have demonstrated that the immunoregulatory pathway of tryptophan catabolism, initiated by the enzyme indoleamine 2,3-dioxygenase (IDO), is a critical participant in allergic inflammation. Originally known for its regulatory function during pregnancy and during chronic inflammation in tumorigenesis and infection, the activity of IDO seems to positively modify the inflammatory state of atopy or allergy. The tryptophan degradation pathway is important for tolerance induction during systemic allergen immunotherapy. Here, we focus on recent findings that establish the IDO pathway as central to allergic inflammation.The indoleamine 2,3-dioxygenase (IDO) pathway has been found to contribute substantially to the control of allergic inflammation. Traditionally recognized for its immunomodulatory role in infection, pregnancy, autoimmunity, and neoplasia, the effect of IDO on allergy appears to be a another piece of puzzle in the 'hygiene hypothesis'. Early microbial exposure and thus the stimulation of the IDO pathway by distinct Toll-like receptors (TLR) may, together with other immunoregulatory pathways, shape the predisposition to and determine the outcome of allergic inflammation, autoimmunity, and probably other diseases. Current data suggest that a normal induction of IDO activity, which decreases serum tryptophan (trp) levels and increases the levels of trp metabolites, controls the allergic inflammation. The mechanism of IDO-induced tolerance induction can probably be manifold but the induction of regulatory T cells may be a major aspect of the control function over allergic inflammation. This review summarizes the current knowledge on the IDO pathway and its role in regulating immune functions with a focus on allergic diseases.Tryptophan and its degradation pathways: indoleamine 2,3-dioxygenase and tryptophan 2,3-dioxygenase (TDO)As an essential amino acid, tryptophan (trp) is a constituent of proteins. Inadequate dietary intake of trp and other essential amino acids can lead to a negative nitrogen balance and to a loss of muscle mass, brain size, and weight (1). Trp is an essential starting point of two biochemical pathways: (i) the enzyme tryptophan 5-hydroxylase converts trp into 5-hydroxytryptophan, which is subsequently decarboxylized to 5-hydroxytryptamine (5-HT, serotonin), an essential neurotransmitter and vasoconstrictor, and (ii) two atoms of the molecular oxygen are inserted into L-trp to form N-formylkynurenine, the first and rate-limiting step in the kynurenine pathway (Fig. 1) (2, 3). The activation of molecular oxygen and its insertion into trp are catalyzed by three

show abstract

Tryptophan Deprivation Induces Inhibitory Receptors ILT3 and ILT4 on Dendritic Cells Favoring the Induction of Human CD4+CD25+ Foxp3+ T Regulatory Cells

Cited by 145 publications

References 56 publications

Regulation of myeloperoxidase‐specific T cell responses during disease remission in antineutrophil cytoplasmic antibody–associated vasculitis: The role of Treg cells and tryptophan degradation

Regulation of myeloperoxidase‐specific T cell responses during disease remission in antineutrophil cytoplasmic antibody–associated vasculitis: The role of Treg cells and tryptophan degradation

Mesenchymal stem cells from periapical lesions modulate differentiation and functional properties of monocyte‐derived dendritic cells

The indoleamine 2,3‐dioxygenase (IDO) pathway controls allergy

Contact Info

Product

Resources

About