Blockade of IDO inhibits nasal tolerance induction

Arnold P J van der Marel, Janneke N Samsom, Mascha Greuter, Lisette A van Berkel, Tom O'Toole, Georg Kraal, Reina E Mebius

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

The amino acid tryptophan is essential for the proliferation and survival of cells. Modulation of tryptophan metabolism has been described as an important regulatory mechanism for the control of immune responses. The enzyme IDO degrades the indole moiety of tryptophan, not only depleting tryptophan but also producing immunomodulatory metabolites called kynurenines, which have apoptosis-inducing capabilities. In this study, we show that IDO is more highly expressed in nonplasmacytoid dendritic cells of the nose draining lymph nodes (LNs), which form a unique environment to induce tolerance to inhaled Ags, when compared with other peripheral LNs. Upon blockade of IDO during intranasal OVA administration, Ag-specific immune tolerance was abrogated. Analysis of Ag-specific T cells in the LNs revealed that inhibition of IDO resulted in enhanced survival at 48 h after antigenic stimulation, although this result was not mediated through alterations in apoptosis or cell proliferation. Furthermore, no differences were found in CD4(+) T cells expressing FoxP3. Our data suggest that the level of IDO expression in dendritic cells, present in nose draining LNs, allows for the generation of a sufficient number of regulatory T cells to control and balance effector T cells in such a way that immune tolerance is induced, whereas upon IDO blockade, effector T cells will outnumber regulatory T cells, leading to immunity.

Original languageEnglish
Pages (from-to)894-900
Number of pages7
JournalJournal of Immunology
Volume179
Issue number2
Publication statusPublished - 15 Jul 2007

Cite this

van der Marel, A. P. J., Samsom, J. N., Greuter, M., van Berkel, L. A., O'Toole, T., Kraal, G., & Mebius, R. E. (2007). Blockade of IDO inhibits nasal tolerance induction. Journal of Immunology, 179(2), 894-900.
van der Marel, Arnold P J ; Samsom, Janneke N ; Greuter, Mascha ; van Berkel, Lisette A ; O'Toole, Tom ; Kraal, Georg ; Mebius, Reina E. / Blockade of IDO inhibits nasal tolerance induction. In: Journal of Immunology. 2007 ; Vol. 179, No. 2. pp. 894-900.
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van der Marel, APJ, Samsom, JN, Greuter, M, van Berkel, LA, O'Toole, T, Kraal, G & Mebius, RE 2007, 'Blockade of IDO inhibits nasal tolerance induction' Journal of Immunology, vol. 179, no. 2, pp. 894-900.

Blockade of IDO inhibits nasal tolerance induction. / van der Marel, Arnold P J; Samsom, Janneke N; Greuter, Mascha; van Berkel, Lisette A; O'Toole, Tom; Kraal, Georg; Mebius, Reina E.

In: Journal of Immunology, Vol. 179, No. 2, 15.07.2007, p. 894-900.

Research output: Contribution to journalArticleAcademicpeer-review

TY - JOUR

T1 - Blockade of IDO inhibits nasal tolerance induction

AU - van der Marel, Arnold P J

AU - Samsom, Janneke N

AU - Greuter, Mascha

AU - van Berkel, Lisette A

AU - O'Toole, Tom

AU - Kraal, Georg

AU - Mebius, Reina E

PY - 2007/7/15

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N2 - The amino acid tryptophan is essential for the proliferation and survival of cells. Modulation of tryptophan metabolism has been described as an important regulatory mechanism for the control of immune responses. The enzyme IDO degrades the indole moiety of tryptophan, not only depleting tryptophan but also producing immunomodulatory metabolites called kynurenines, which have apoptosis-inducing capabilities. In this study, we show that IDO is more highly expressed in nonplasmacytoid dendritic cells of the nose draining lymph nodes (LNs), which form a unique environment to induce tolerance to inhaled Ags, when compared with other peripheral LNs. Upon blockade of IDO during intranasal OVA administration, Ag-specific immune tolerance was abrogated. Analysis of Ag-specific T cells in the LNs revealed that inhibition of IDO resulted in enhanced survival at 48 h after antigenic stimulation, although this result was not mediated through alterations in apoptosis or cell proliferation. Furthermore, no differences were found in CD4(+) T cells expressing FoxP3. Our data suggest that the level of IDO expression in dendritic cells, present in nose draining LNs, allows for the generation of a sufficient number of regulatory T cells to control and balance effector T cells in such a way that immune tolerance is induced, whereas upon IDO blockade, effector T cells will outnumber regulatory T cells, leading to immunity.

AB - The amino acid tryptophan is essential for the proliferation and survival of cells. Modulation of tryptophan metabolism has been described as an important regulatory mechanism for the control of immune responses. The enzyme IDO degrades the indole moiety of tryptophan, not only depleting tryptophan but also producing immunomodulatory metabolites called kynurenines, which have apoptosis-inducing capabilities. In this study, we show that IDO is more highly expressed in nonplasmacytoid dendritic cells of the nose draining lymph nodes (LNs), which form a unique environment to induce tolerance to inhaled Ags, when compared with other peripheral LNs. Upon blockade of IDO during intranasal OVA administration, Ag-specific immune tolerance was abrogated. Analysis of Ag-specific T cells in the LNs revealed that inhibition of IDO resulted in enhanced survival at 48 h after antigenic stimulation, although this result was not mediated through alterations in apoptosis or cell proliferation. Furthermore, no differences were found in CD4(+) T cells expressing FoxP3. Our data suggest that the level of IDO expression in dendritic cells, present in nose draining LNs, allows for the generation of a sufficient number of regulatory T cells to control and balance effector T cells in such a way that immune tolerance is induced, whereas upon IDO blockade, effector T cells will outnumber regulatory T cells, leading to immunity.

KW - Administration, Intranasal

KW - Adoptive Transfer

KW - Animals

KW - Dendritic Cells/enzymology

KW - Female

KW - Forkhead Transcription Factors/biosynthesis

KW - Immune Tolerance/physiology

KW - Indoleamine-Pyrrole 2,3,-Dioxygenase/immunology

KW - Lymph Nodes/cytology

KW - Mice

KW - Mice, Inbred BALB C

KW - Nasal Mucosa/immunology

KW - Ovalbumin/administration & dosage

KW - Reverse Transcriptase Polymerase Chain Reaction

KW - T-Lymphocytes/immunology

M3 - Article

VL - 179

SP - 894

EP - 900

JO - Journal of Immunology

JF - Journal of Immunology

SN - 0022-1767

IS - 2

ER -

van der Marel APJ, Samsom JN, Greuter M, van Berkel LA, O'Toole T, Kraal G et al. Blockade of IDO inhibits nasal tolerance induction. Journal of Immunology. 2007 Jul 15;179(2):894-900.