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Blood, 15 February 2005, Vol. 105, No. 4, pp. 1574-1581.
Prepublished online as a Blood First Edition Paper on October 5, 2004; DOI 10.1182/blood-2004-06-2089.
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IMMUNOBIOLOGY
Regulation of indoleamine 2,3-dioxygenase and tryptophanyl-tRNA-synthetase by CTLA-4-Fc in human CD4+ T cells
Adriano Boasso,
Jean-Philippe Herbeuval,
Andrew W. Hardy,
Christiana Winkler, and
Gene M. Shearer
From the Experimental Immunology Branch, Center for Cancer Research (CCR), National Cancer Institute (NCI), National Institutes of Health (NIH), Bethesda, MD; the Institute for Medical Chemistry and Biochemistry, Innsbruck Medical University; and Ludwig Boltzmann Institute of AIDS-Research, Innsbruck, Austria.
Indoleamine-2,3-dioxygenase (IDO) and tryptophanyl-tRNA-synthetase (TTS) are interferon- (IFN-)–inducible enzymes that are responsible for tryptophan degradation and for its use in protein synthesis, respectively. IFN-–induced IDO has immunomodulatory properties in murine and human models. A concomitant increase of TTS has been postulated to protect the IDO-expressing cells from tryptophan catabolism. IDO can be induced in dendritic cells (DCs) by recombinant soluble cytotoxic T lymphocyte antigen-4 (CTLA-4-Fc). We investigated the effects of CTLA-4-Fc on IDO and TTS mRNA expression in human peripheral blood mononuclear cells (PBMCs) and isolated leukocyte subsets. CTLA-4-Fc exposure induced increased IDO and TTS expression in unseparated PBMCs, as well as in monocyte-derived mature DCs. CD4+ T cells isolated from CTLA-4-Fc–treated PBMCs showed increased IDO and TTS compared with untreated cells. CD8+ T cells from CTLA-4-Fc–treated PBMCs expressed increased levels of TTS but not IDO. Pretreatment of PBMCs with CTLA-4-Fc inhibited the activation of CD4+ T cells induced by influenza A virus (Flu) or phytohemagglutinin A (PHA), but had no effect on CD8+ T cells. This is the first report of IDO and TTS regulation by the CTLA-4-B7 system in human CD4+ and CD8+ T cells, and raises the possibility that these 2 tryptophan-modulating enzymes provide an important mechanism for regulating immune responses.
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