The combined effects of tryptophan starvation and tryptophan catabolites down-regulate T cell receptor ζ-chain and induce a regulatory phenotype in naive T cells

Francesca Fallarino, Ursula Grohmann, Sylvaine You, Barbara Claire McGrath, Douglas R. Cavener, Carmine Vacca, Ciriana Orabona, Roberta Bianchi, Maria L. Belladonna, Claudia Volpi, Pere Santamaria, Maria C. Fioretti, Paolo Puccetti

Research output: Contribution to journalArticle

606 Citations (Scopus)

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 the short-term, combined effects of tryptophan deprivation and tryptophan catabolites result in GCN2 kinase-dependent down-regulation of the TCR ζ-chain in murine CD8 + T cells. TCR ζ down-regulation can be demonstrated in vivo and is associated with an impaired cytotoxic effector function in vitro. The longer-term effects of tryptophan catabolism include the emergence of a regulatory phenotype in naive CD4+CD25- T cells via TGF-β induction of the forkhead transcription factor Foxp3. Such converted cells appear to be CD25+, CD69-, CD45RBlow, CD62L+, CTLA-4+, BTLAlow and GITR+, and are capable of effective control of diabetogenic T cells when transferred in vivo. Thus, both tryptophan starvation and tryptophan catabolites contribute to establishing a regulatory environment affecting CD8+ as well as CD4+ T cell function, and not only is tryptophan catabolism an effector mechanism of tolerance, but it also results in GCN2-dependent generation of autoimmune-preventive regulatory T cells.

Original languageEnglish (US)
Pages (from-to)6752-6761
Number of pages10
JournalJournal of Immunology
Volume176
Issue number11
StatePublished - Jun 1 2006

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T-Cell Antigen Receptor
Starvation
Down-Regulation
Tryptophan
T-Lymphocytes
Phenotype
Regulatory T-Lymphocytes
Forkhead Transcription Factors
Phosphotransferases
tryptophyltryptophan

All Science Journal Classification (ASJC) codes

  • Immunology

Cite this

Fallarino, Francesca ; Grohmann, Ursula ; You, Sylvaine ; McGrath, Barbara Claire ; Cavener, Douglas R. ; Vacca, Carmine ; Orabona, Ciriana ; Bianchi, Roberta ; Belladonna, Maria L. ; Volpi, Claudia ; Santamaria, Pere ; Fioretti, Maria C. ; Puccetti, Paolo. / The combined effects of tryptophan starvation and tryptophan catabolites down-regulate T cell receptor ζ-chain and induce a regulatory phenotype in naive T cells. In: Journal of Immunology. 2006 ; Vol. 176, No. 11. pp. 6752-6761.
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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 the short-term, combined effects of tryptophan deprivation and tryptophan catabolites result in GCN2 kinase-dependent down-regulation of the TCR ζ-chain in murine CD8 + T cells. TCR ζ down-regulation can be demonstrated in vivo and is associated with an impaired cytotoxic effector function in vitro. The longer-term effects of tryptophan catabolism include the emergence of a regulatory phenotype in naive CD4+CD25- T cells via TGF-β induction of the forkhead transcription factor Foxp3. Such converted cells appear to be CD25+, CD69-, CD45RBlow, CD62L+, CTLA-4+, BTLAlow and GITR+, and are capable of effective control of diabetogenic T cells when transferred in vivo. Thus, both tryptophan starvation and tryptophan catabolites contribute to establishing a regulatory environment affecting CD8+ as well as CD4+ T cell function, and not only is tryptophan catabolism an effector mechanism of tolerance, but it also results in GCN2-dependent generation of autoimmune-preventive regulatory T cells.",
author = "Francesca Fallarino and Ursula Grohmann and Sylvaine You and McGrath, {Barbara Claire} and Cavener, {Douglas R.} and Carmine Vacca and Ciriana Orabona and Roberta Bianchi and Belladonna, {Maria L.} and Claudia Volpi and Pere Santamaria and Fioretti, {Maria C.} and Paolo Puccetti",
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Fallarino, F, Grohmann, U, You, S, McGrath, BC, Cavener, DR, Vacca, C, Orabona, C, Bianchi, R, Belladonna, ML, Volpi, C, Santamaria, P, Fioretti, MC & Puccetti, P 2006, 'The combined effects of tryptophan starvation and tryptophan catabolites down-regulate T cell receptor ζ-chain and induce a regulatory phenotype in naive T cells', Journal of Immunology, vol. 176, no. 11, pp. 6752-6761.

The combined effects of tryptophan starvation and tryptophan catabolites down-regulate T cell receptor ζ-chain and induce a regulatory phenotype in naive T cells. / Fallarino, Francesca; Grohmann, Ursula; You, Sylvaine; McGrath, Barbara Claire; Cavener, Douglas R.; Vacca, Carmine; Orabona, Ciriana; Bianchi, Roberta; Belladonna, Maria L.; Volpi, Claudia; Santamaria, Pere; Fioretti, Maria C.; Puccetti, Paolo.

In: Journal of Immunology, Vol. 176, No. 11, 01.06.2006, p. 6752-6761.

Research output: Contribution to journalArticle

TY - JOUR

T1 - The combined effects of tryptophan starvation and tryptophan catabolites down-regulate T cell receptor ζ-chain and induce a regulatory phenotype in naive T cells

AU - Fallarino, Francesca

AU - Grohmann, Ursula

AU - You, Sylvaine

AU - McGrath, Barbara Claire

AU - Cavener, Douglas R.

AU - Vacca, Carmine

AU - Orabona, Ciriana

AU - Bianchi, Roberta

AU - Belladonna, Maria L.

AU - Volpi, Claudia

AU - Santamaria, Pere

AU - Fioretti, Maria C.

AU - Puccetti, Paolo

PY - 2006/6/1

Y1 - 2006/6/1

N2 - 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 the short-term, combined effects of tryptophan deprivation and tryptophan catabolites result in GCN2 kinase-dependent down-regulation of the TCR ζ-chain in murine CD8 + T cells. TCR ζ down-regulation can be demonstrated in vivo and is associated with an impaired cytotoxic effector function in vitro. The longer-term effects of tryptophan catabolism include the emergence of a regulatory phenotype in naive CD4+CD25- T cells via TGF-β induction of the forkhead transcription factor Foxp3. Such converted cells appear to be CD25+, CD69-, CD45RBlow, CD62L+, CTLA-4+, BTLAlow and GITR+, and are capable of effective control of diabetogenic T cells when transferred in vivo. Thus, both tryptophan starvation and tryptophan catabolites contribute to establishing a regulatory environment affecting CD8+ as well as CD4+ T cell function, and not only is tryptophan catabolism an effector mechanism of tolerance, but it also results in GCN2-dependent generation of autoimmune-preventive regulatory T cells.

AB - 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 the short-term, combined effects of tryptophan deprivation and tryptophan catabolites result in GCN2 kinase-dependent down-regulation of the TCR ζ-chain in murine CD8 + T cells. TCR ζ down-regulation can be demonstrated in vivo and is associated with an impaired cytotoxic effector function in vitro. The longer-term effects of tryptophan catabolism include the emergence of a regulatory phenotype in naive CD4+CD25- T cells via TGF-β induction of the forkhead transcription factor Foxp3. Such converted cells appear to be CD25+, CD69-, CD45RBlow, CD62L+, CTLA-4+, BTLAlow and GITR+, and are capable of effective control of diabetogenic T cells when transferred in vivo. Thus, both tryptophan starvation and tryptophan catabolites contribute to establishing a regulatory environment affecting CD8+ as well as CD4+ T cell function, and not only is tryptophan catabolism an effector mechanism of tolerance, but it also results in GCN2-dependent generation of autoimmune-preventive regulatory T cells.

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