IDO Upregulates Regulatory T Cells via Tryptophan Catabolite and Suppresses Encephalitogenic T Cell Responses in Experimental Autoimmune Encephalomyelitis

Abstract

Experimental autoimmune encephalomyelitis (EAE) is a Th1 and Th17 cell-mediated autoimmune disease of the CNS. IDO and tryptophan metabolites have inhibitory effects on Th1 cells in EAE. For Th17 cells, IDO-mediated tryptophan deprivation and small molecule halofuginone-induced amino acid starvation response were shown to activate general control nonrepressed 2 (GCN2) kinase that directly or indirectly inhibits Th17 cell differentiation. However, it remains unclear whether IDO and tryptophan metabolites impact the Th17 cell response by mechanisms other than the GCN2 kinase pathway. In this article, we show that IDO-deficient mice develop exacerbated EAE with enhanced encephalitogenic Th1 and Th17 cell responses and reduced regulatory T cell (Treg) responses. Administration of the downstream tryptophan metabolite 3-hydroxyanthranillic acid (3-HAA) enhanced the percentage of Tregs, inhibited Th1 and Th17 cells, and ameliorated EAE. We further demonstrate that Th17 cells are less sensitive to direct suppression by 3-HAA than are Th1 cells. 3-HAA treatment in vitro reduced IL-6 production by activated spleen cells and increased expression of TGF-β in dendritic cells (DCs), which correlated with enhanced levels of Tregs, suggesting that 3-HAA–induced Tregs contribute to inhibition of Th17 cells. By using a DC–T cell coculture, we found that 3-HAA–treated DCs expressed higher levels of TGF-β and had properties to induce generation of Tregs from anti-CD3/anti-CD28–stimulated naive CD4+ T cells. Thus, our data support the hypothesis that IDO induces the generation of Tregs via tryptophan metabolites, such as 3-HAA, which enhances TGF-β expression from DCs and promotes Treg differentiation.

A Comparative Study of Stress-mediated Immunological Functions with the Adjuvanticity of Alum

“…Indeed, indoleamine 2, 3-dioxygenase (IDO), which is expressed in some DC and macrophages and play an important role in promoting the formation of T regulatory cells. IDO induces tryptophan depletion and cell stress, which activates the general control nonrepressed 2 (GCN2) protein kinase-dependent pathway and has direct regulatory effect on cell survival and function of immune responses (41)(42)(43). Preliminary studies suggest that human monocyte derived DC treated with the stress inducing agents used in this study inhibit Treg formation.…”

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

“…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].…”

“…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.…”

Quantitative profiling of tryptophan metabolites in serum, urine, and cell culture supernatants by liquid chromatography–tandem mass spectrometry

“…Underlined metabolites were measured by the LC-MS/MS method described amide (NAm) and nicotinic acid (NA) [6]. Most catabolites are biologically active and involved in the pathogenesis of many disease processes [7][8][9][10][11][12]. Furthermore, the interrelationship between metabolic pathways is of profound pharmacological and physiological importance as changes in one pathway might have secondary effects on the others [1].…”