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.
Pubmed ID: 16709834 RIS Download
Mesh terms: Animals | Antigens, CD | Antigens, Differentiation | CD8-Positive T-Lymphocytes | CTLA-4 Antigen | Cells, Cultured | Coculture Techniques | Down-Regulation | Female | Forkhead Transcription Factors | Immunophenotyping | Interleukin-10 | Kynurenine | Membrane Proteins | Mice | Mice, Inbred DBA | Mice, Inbred NOD | Mice, Knockout | Mice, SCID | Mice, Transgenic | Protein Kinases | Protein-Serine-Threonine Kinases | Receptors, Antigen, T-Cell | Receptors, Interleukin-2 | Resting Phase, Cell Cycle | T-Lymphocyte Subsets | T-Lymphocytes, Regulatory | Transforming Growth Factor beta | Tryptophan
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