Tryptophan catabolism generates autoimmune-preventive regulatory T cells

doi:10.1016/j.trim.2006.09.017

Transplant Immunology

Volume 17, Issue 1, December 2006, Pages 58-60

https://doi.org/10.1016/j.trim.2006.09.017 Get rights and content

Abstract

Tryptophan catabolism is a tolerogenic effector system in regulatory T cell function, yet the general mechanisms whereby tryptophan catabolism affects T cell responses remain unclear. We provide evidence that its effects include the emergence of a regulatory phenotype in naive CD4⁺CD25⁻ cells via the general control non-depressing 2 (GCN2) protein kinase mediated induction of the forkhead transcription factor Foxp3. These cells are capable of effective control of diabetogenic T cells in vivo.

Introduction

Indoleamine 2,3-dioxygenase (IDO) is an immunoregulatory enzyme that mediates conversion of the essential amino acid tryptophan to metabolic byproducts collectively known as kynurenines [1], [2]. Modulation of tryptophan catabolism is thought to function as a general mechanism of action of regulatory T (T reg) cells that express cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) [3]. T reg cells are crucial in regulating self-reactive T cells in the periphery and in ameliorating established inflammation in experimental models [4]. Successful treatment of autoimmune neuroinflammation with a synthetic tryptophan metabolite, associated with the development of T reg activity, has recently been reported [5]. One possibility is that IDO contributes to fine-tuning immune responsiveness by several mechanisms that are coordinate but differentiated for specific T cell subsets.

Section snippets

Objective

Here, we describe that IDO-competent cells contribute to the induction of a tolerogenic phenotype in naive CD4⁺ T cells. The effect requires the protein kinase GCN2, which is responsive to starvation for amino acids, and is sustained by the combined actions of tryptophan deprivation and tryptophan catabolites.

Mice

Eight- to 10-week-old DBA/2 (H-2d) and 4-week-old NOD mice were purchased from Charles River Laboratories. Gcn2^−/− mice, homozygous for the GCN2 targeted mutation, and wild-type Gcn2^+/+ controls were as described [6]. NOD-SCID mice were bred in our animal facility under specific pathogen-free conditions to be used at the age of 8–10 weeks. Transgenic BDC2.5/NOD mice [7] were as described. Colorimetric strips were used to monitor glycosuria and hyperglycemia (> 300 mg/dl) in NOD-SCID mice [8].

Tryptophan catabolism converts CD4⁺ Foxp3⁻ into CD4⁺Foxp3⁺ cells by a GCN2-dependent mechanism

We have previously shown that, contrary to T helper type 1 cells, naive T cells do not undergo apoptosis when cultured with IDO⁺ DCs for 48 h [9]. Therefore we investigated whether the continued exposure to IDO⁺ DCs might act on naive CD4⁺ T cells to progressively change their functional properties. Accumulating evidence suggests that T reg cells (CD4⁺CD25⁺ T cells) represent a dedicated T cell lineage characterized by the expression of the forkhead family transcription factor Foxp3 [4]. We

Discussion

CD4⁺CD25⁺ T reg cells are crucial in controlling autoimmune and inflammatory pathology, but little is known about their development and maintenance. Although it appears very likely that most CD4⁺CD25⁺ T reg cell development occurs in the thymus, accumulating evidence suggests that these cells can also develop in the periphery [11]. We found that mature peripheral CD4⁺CD25⁻ T cells can indeed convert to a T reg phenotype through an IDO-mediated process requiring the GCN2 kinase. The converted

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There are more references available in the full text version of this article.

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Brief communicationTryptophan catabolism generates autoimmune-preventive regulatory T cells

Abstract

Introduction

Section snippets

Objective

Mice

Tryptophan catabolism converts CD4+ Foxp3− into CD4+Foxp3+ cells by a GCN2-dependent mechanism

Discussion

Trends Immunol

Immunity

IDO expression by dendritic cells: tolerance and tryptophan catabolism

Nat Rev Immunol

Modulation of tryptophan catabolism by regulatory T cells

Nat Immunol

Naturally arising Foxp3-expressing CD25+CD4+ regulatory T cells in immunological tolerance to self and non-self

Nat Immunol

Treatment of autoimmune neuroinflammation with a synthetic tryptophan metabolite

Science

Brief communication
Tryptophan catabolism generates autoimmune-preventive regulatory T cells

Tryptophan catabolism converts CD4⁺ Foxp3⁻ into CD4⁺Foxp3⁺ cells by a GCN2-dependent mechanism

Naturally arising Foxp3-expressing CD25⁺CD4⁺ regulatory T cells in immunological tolerance to self and non-self