The combined effects of tryptophan starvation and tryptophan catabolites down-regulate T cell receptor zeta-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 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.
Fallarino
Francesca
F
Department of Experimental Medicine, University of Perugia, Perugia, Italy.
Grohmann
Ursula
U
You
Sylvaine
S
McGrath
Barbara C
BC
Cavener
Douglas R
DR
Vacca
Carmine
C
Orabona
Ciriana
C
Bianchi
Roberta
R
Belladonna
Maria L
ML
Volpi
Claudia
C
Santamaria
Pere
P
Fioretti
Maria C
MC
Puccetti
Paolo
P
D000818:Animals; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000502:physiology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D060908:CTLA-4 Antigen; D002478:Cells, Cultured; D018920:Coculture Techniques; D015536:Down-Regulation / Q000276:immunology*; D005260:Female; D051858:Forkhead Transcription Factors / Q000096:biosynthesis / Q000378:metabolism; D016130:Immunophenotyping; D016753:Interleukin-10 / Q000502:physiology; D007737:Kynurenine / Q000378:metabolism / Q000494:pharmacology; D008565:Membrane Proteins / Q000037:antagonists & inhibitors* / Q000096:biosynthesis*; D051379:Mice; D008811:Mice, Inbred DBA; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D016513:Mice, SCID; D008822:Mice, Transgenic; D011494:Protein Kinases / Q000502:physiology; D017346:Protein Serine-Threonine Kinases; D011948:Receptors, Antigen, T-Cell / Q000037:antagonists & inhibitors* / Q000096:biosynthesis*; D015375:Receptors, Interleukin-2 / Q000096:biosynthesis / Q000378:metabolism; D016192:Resting Phase, Cell Cycle / Q000276:immunology*; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000502:physiology; D014364:Tryptophan / Q000378:metabolism* / Q000502:physiology
D015703:Antigens, CD; D000943:Antigens, Differentiation; D060908:CTLA-4 Antigen; C556707:Ctla4 protein, mouse; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D008565:Membrane Proteins; D011948:Receptors, Antigen, T-Cell; D015375:Receptors, Interleukin-2; D016212:Transforming Growth Factor beta; C054979:antigen T cell receptor, zeta chain; D016753:Interleukin-10; D007737:Kynurenine; D014364:Tryptophan; D011494:Protein Kinases; C070634:Eif2ak4 protein, mouse; D017346:Protein Serine-Threonine Kinases