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

作者：Francesca Fallarino, Ursula Grohmann, Sylvaine You, Barbara C. McGrath, Douglas R. Cavener, Carmine Vacca, Ciriana Orabona, Roberta Bianchi, Maria Laura Belladonna, Claudia Volpi, Pere Santamaría, Maria C. Fioretti, Paolo Puccetti · 发表于：The Journal of Immunology · 年份：2006 · DOI：10.4049/jimmunol.176.11.6752 · 被引用次数：1049 · 研究领域：Immune Cell Function and Interaction、T-cell and B-cell Immunology、Diabetes and associated disorders

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 zeta-chain in murine CD8+ T cells. TCR zeta 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-beta 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.