Tryptophan deprivation sensitizes activated T cells to apoptosis prior to cell division

Geon Kook Lee, Hyeon Jin Park, Megan MacLeod, Phillip Chandler, David H. Munn, Andrew L. Mellor

Research output: Contribution to journalArticle

242 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)452-460
Number of pages9
JournalImmunology
Volume107
Issue number4
DOIs
Publication statusPublished - Dec 1 2002

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ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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