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

F Fallarino, U Grohmann, S You… - The Journal of …, 2006 - journals.aai.org
The Journal of Immunology, 2006journals.aai.org
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 …
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−, CD45RB low, CD62L+, CTLA-4+, BTLA low 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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