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  • Review Article
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Ido expression by dendritic cells: tolerance and tryptophan catabolism

Nature Reviews Immunology volume 4, pages 762–774 (2004)Cite this article

Key Points

  • The peripheral immune system can promote either immunity or tolerance when presented with new antigens. Dendritic cells (DCs) have a crucial role in determining immune outcomes by acquiring antigens, collating environmental cues and then becoming cells that are either potent stimulators or suppressors of T-cell responses.

  • Enzymatic activity of indoleamine 2,3-dioxygenase (IDO) correlates with reduced T-cell-mediated responses in several experimental (mouse) systems, including models of autoimmune diseases, cancer, organ and tissue transplant rejection, and pregnancy.

  • IDO is a haeme-containing enzyme that catabolizes compounds containing indole rings, such as the essential amino acid tryptophan. IDO protein is encoded by a tightly regulated gene that is responsive to inflammatory mediators in a limited range of cell types.

  • Mature DCs that express functional IDO enzyme activity can be potent suppressors of T-cell responses in vivo and in vitro.

  • Ligation of CD80/CD86 molecules, which are normally thought of as co-stimulatory molecules on DCs, induces the expression of functional IDO by certain subsets of DCs (IDO-competent DCs); other DC subsets, and other antigen-presenting cell types that express CD80/CD86 do not express IDO after CD80/CD86 ligation.

  • The synthetic immunomodulatory reagent cytotoxic T lymphocyte antigen 4 (CTLA4)–immunoglobulin fusion protein is a potent inducer of IDO expression by DCs.

  • Regulatory T cells that express CTLA4 induce IDO-competent DCs to express IDO, indicating that CTLA4+ regulatory T cells use the IDO mechanism to suppress T-cell responses and promote tolerance.

  • More speculatively, IDO-expressing DCs might promote the development of regulatory T cells; if so, regulatory T cells and IDO-competent DCs might cooperate to form a self-amplifying immunoregulatory network.

Abstract

Indoleamine 2,3-dioxygenase (IDO) is an enzyme that degrades the essential amino acid tryptophan. The concept that cells expressing IDO can suppress T-cell responses and promote tolerance is a relatively new paradigm in immunology. Considerable evidence now supports this hypothesis, including studies of mammalian pregnancy, tumour resistance, chronic infections and autoimmune diseases. In this review, we summarize key recent developments and propose a unifying model for the role of IDO in tolerance induction.

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Figure 1: Pivotal role of dendritic cells in deciding tolerance versus immunity.
Figure 2: Indoleamine 2,3-dioxygenase molecular genetics and enzyme activity.
Figure 3: Maturation of indoleamine 2,3-dioxygenase-competent dendritic cells.
Figure 4: Potential downstream mechanisms of indoleamine 2,3-dioxygenase.

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Acknowledgements

We acknowledge the National Institutes of Health for supporting the research described in this review.

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Authors and Affiliations

  1. Departments of Medicine and Pediatrics, Program in Molecular Immunology, Institute of Molecular Medicine and Genetics, Medical College of Georgia, Augusta, 30912, Georgia, USA

    Andrew L. Mellor & David H. Munn

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Correspondence to Andrew L. Mellor.

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DATABASES

Entrez Gene

CD8α

CD80

CD86

CTLA4

GCN2

IDO

IFN-γ

IL-1

IL-10

IRF1

mTOR

STAT1

TDO

TGF-β

TNF

Glossary

ANTIGENICITY

The ability to be recognized by the immune system by binding to T- and B-cell receptors, although this might not result in overt immune responses.

IMMUNOGENICITY

The ability to provoke overt immune responses.

ESSENTIAL AMINO ACIDS

Amino acids that cannot be synthesized by cells and must be acquired in the diet. Tryptophan is energetically unfavourable to synthesize and even organisms that can synthesize tryptophan will take it up in preference to synthesizing it.

APOENZYME

The protein component of an enzyme that requires additional co-factors to become active (holoenzyme).

TROPHOBLAST GIANT CELLS

(TGCs). Cells of fetal origin in mouse extra-embryonic tissues that develop into large cells through marked amplification of DNA content coupled with cytoplasmic expansion. Primary TGCs line the outer surfaces of the fetal–placental unit at midgestation in mice. Secondary TGCs migrate into the maternal deciduas at later times during mouse gestation.

EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS

An experimental model for the human disease multiple sclerosis. Autoimmune disease is induced in experimental animals by immunization with myelin antigen or peptides derived from myelin. The animals develop a paralytic disease with inflammation and demyelination in the brain and spinal cord.

GRAFT-VERSUS-HOST-DISEASE

(GVHD). An immune response mounted against the recipient of an allograft by immunocompetent T cells that are derived from the graft. Typically, it is seen in the context of allogeneic bone-marrow transplantation.

NITRIC OXIDE SYNTHASE

An inducible haeme-containing enzyme that produces nitric oxide in response to inflammatory signals.

LINKED SUPPRESSION

The phenomenon of suppressing responses to a specific antigen by co-presenting it simultaneously with another antigen, against which tolerance has previously been established.

INFECTIOUS TOLERANCE

The ability of a tolerized population of T cells to induce tolerance in a new, naive population of T cells. Tolerance might be to the same antigens or to new antigens that are encountered in the same context (linked suppression). Newly tolerized T cells can, in turn, induce tolerance of other T cells.

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Mellor, A., Munn, D. Ido expression by dendritic cells: tolerance and tryptophan catabolism. Nat Rev Immunol 4, 762–774 (2004). https://doi.org/10.1038/nri1457

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