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

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…

• FP
  Fondation pour la Recherche Médicale
• AI
  Associazione Italiana per la Ricerca sul Cancro
• CI
  Canadian Institutes of Health Research