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-Chain and Induce a Regulatory Phenotype in Naive T Cells1
* Department of Experimental Medicine, University of Perugia, Perugia, Italy;
Institut National de la Santé et de la Recherche Médicale Unité 580-Institut Fédératif de Recherche Necker Enfants-Malades, Hôpital Necker, Paris, France;
Department of Biology, The Pennsylvania State University, University Park, PA 16802; and
Julia McFarlane Diabetes Research Centre, University of Calgary, Calgary, Alberta, Canada
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 
-chain in murine CD8+ T cells. TCR 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-
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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