Tryptophan deprivation sensitizes activated T cells to apoptosis prior to cell division.
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.
Lee
Geon Kook
GK
Program in Molecular Immunology, Institute of Molecular Medicine and Genetics, Medical College of Georgia, Augusta, GA 30912, USA.
Park
Hyeon Jin
HJ
Macleod
Megan
M
Chandler
Phillip
P
Munn
David H
DH
Mellor
Andrew L
AL
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
D015703:Antigens, CD; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D014364:Tryptophan; D014366:Tryptophan Oxygenase