title: Tryptophan deprivation sensitizes activated T cells to apoptosis prior to cell division.
abstract: Cells expressing indoleamine 2,3-dioxygenase (IDO), an enzyme which catabolizes tryptophan, prevent T-cell proliferation in vitro, suppress maternal antifetal immunity during pregnancy and inhibit T-cell-mediated responses to tumour-associated antigens. To examine the mechanistic basis of these phenomena we activated naïve murine T cells in chemically defined tryptophan-free media. Under these conditions T cells expressed CD25 and CD69 and progressed through the first 12 hr of G0/G1 phase but did not express CD71, cyclin D3, cdk4, begin DNA synthesis, or differentiate into cytotoxic effector cells. In addition, activated T cells with their growth arrested by tryptophan deprivation exhibited enhanced tendencies to die via apoptosis when exposed to anti-Fas antibodies. Apoptosis was inhibited by caspase inhibitor and was not observed when T cells originated from Fas-deficient mice. These findings suggest that T cells activated in the absence of free tryptophan entered the cell cycle but cell cycle progression ceased in mid-G1 phase and T cells became susceptible to death via apoptosis, in part though Fas-mediated signalling. Thus, mature antigen-presenting cells expressing IDO and Fas-ligand may induce antigen-specific T-cell tolerance by blocking T-cell cycle progression and by rapid induction of T-cell activation induced cell death in local tissue microenvironments.
authors.affiliation: Program in Molecular Immunology, Institute of Molecular Medicine and Genetics, Medical College of Georgia, Augusta, GA 30912, USA.
authors.forename: Geon Kook
authors.initials: GK
authors.lastname: Lee
authors.forename: Hyeon Jin
authors.initials: HJ
authors.lastname: Park
authors.forename: Megan
authors.initials: M
authors.lastname: Macleod
authors.forename: Phillip
authors.initials: P
authors.lastname: Chandler
authors.forename: David H
authors.initials: DH
authors.lastname: Munn
authors.forename: Andrew L
authors.initials: AL
authors.lastname: Mellor
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000276:immunology; D017209:Apoptosis / Q000276:immunology*; D015153:Blotting, Western / Q000379:methods; D002455:Cell Division / Q000276:immunology; D002460:Cell Line / Q000276:immunology; D003602:Cytotoxicity, Immunologic / Q000276:immunology; D005434:Flow Cytometry / Q000379:methods; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D007399:Interphase / Q000276:immunology; D051379:Mice; D008808:Mice, Inbred CBA; D008822:Mice, Transgenic; D016196:S Phase / Q000276:immunology; D013154:Spleen / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology*; D014364:Tryptophan / Q000172:deficiency*; D014366:Tryptophan Oxygenase / Q000276:immunology
chemical_list: D015703:Antigens, CD; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D014364:Tryptophan; D014366:Tryptophan Oxygenase