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IDO-expressing regulatory dendritic cells in cancer and chronic infection

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Abstract

Immune evasion and T cell tolerance induction have been associated both with malignant disease and chronic infection. In recent years, increasing evidence has been accumulated that antigen-presenting cells such as dendritic cells (DC) play a major role in immune regulation. They are not only involved in the induction of immunity but also can inhibit immune responses. Interesting parallels for major molecular mechanisms involved in turning DC from stimulatory to regulatory cells have been uncovered between malignant disease and chronic infection. Apparently, not only inhibitory cytokines such as IL-10 seem to play a role, but also metabolic mechanisms dysregulating tryptophan metabolism, thereby, leading to inhibition of T cells and pathogens. We focus here on recent findings establishing the tryptophan catabolizing enzyme indoleamine-pyrrole 2,3 dioxygenase (IDO) as a central feature of DC with regulatory function both in cancer and chronic infection. Induction of enzymatically active IDO can be triggered by various soluble and membrane-bound factors, and in general, require interferon (IFN) signaling. In addition, based on the most recently established link between tumor necrosis factor alpha (TNFα), prostaglandin E2 and IDO, a new model of regulation of IDO in context of cancer and infection is proposed. In light of the increasing use of anti-TNFα drugs, these findings are also of great interest to the clinician scientist.

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Abbreviations

APC:

antigen-presenting cells

BDCA:

blood dendritic cell antigen

COX-2:

cyclooxygenase-2

CTLs:

cytotoxic T lymphocytes

DC:

dendritic cells

DCreg :

regulatory dendritic cells

EP2:

prostaglandin E2 receptor 2

FoxP3:

Forkhead box P3

GITR:

glucocorticoid-induced tumor necrosis factor receptor

HIV:

human immunodeficiency virus

HO-1:

heme oxygenase-1

ICSBP1:

interferon consensus sequence-binding protein 1

IDO:

indoleamine-pyrrole 2,3 dioxygenase (INDO)

IFN:

interferon

ILT:

immunologlobulin-like transcripts

INOS:

inducible nitric oxide synthase

IRF-1:

interferon regulatory factor 1

ISRE:

interferon-stimulated response elements

Mo-DC:

monocyte-derived DC

MS:

multiple sclerosis, pDC-plasmacytoid DC

PGE2 :

prostaglandin E2

RA:

rheumatoid arthritis

SOCS3:

suppressor of cytokine signaling 3

STAT:

signal transducer and activator of transcription

TDLN:

tumor-draining lymph nodes

TLR:

toll-like receptor

Tregs:

regulatory T cells

TYROBP:

tyro protein tyrosine kinase-binding protein

VEGF:

vascular endothelial growth factor.

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Acknowledgments

This work was supported by a Sofja Kovalevskaja Award from the Alexander von Humboldt Foundation, a Köln Fortune Grant and a grant of the Bundesministerium fuer Bildung and Forschung (NGFN N1K3-S24T27) to JLS.

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  1. Molecular Tumor Biology and Tumor Immunology, Clinic I for Internal Medicine, Cologne, Germany

    Alexey Popov & Joachim L. Schultze

  2. Cologne Center for Genomics, University of Cologne, Cologne, Germany

    Joachim L. Schultze

  3. Molekulare Tumorbiologie und Tumorimmunologie, Klinik I für Innere Medizin, Universitätsklinikum Köln, Kerpener Str. 62/ Haus 16 UG, 50924, Köln, Germany

    Joachim L. Schultze

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Popov, A., Schultze, J.L. IDO-expressing regulatory dendritic cells in cancer and chronic infection. J Mol Med 86, 145–160 (2008). https://doi.org/10.1007/s00109-007-0262-6

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