Regulation of indoleamine 2,3-dioxygenase and tryptophanyl-tRNA-synthetase by CTLA-4-Fc in human CD4+ T cells.
Indoleamine-2,3-dioxygenase (IDO) and tryptophanyl-tRNA-synthetase (TTS) are interferon-gamma (IFN-gamma)-inducible enzymes that are responsible for tryptophan degradation and for its use in protein synthesis, respectively. IFN-gamma-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.
Experimental Immunology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Adriano
A
Boasso
Jean-Philippe
JP
Herbeuval
Andrew W
AW
Hardy
Christiana
C
Winkler
Gene M
GM
Shearer
D000069594:Abatacept; D015703:Antigens, CD / Q000378:metabolism; D018122:B7-1 Antigen / Q000378:metabolism; D051940:B7-2 Antigen; D015496:CD4-Positive T-Lymphocytes / Q000201:enzymology* / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000201:enzymology / Q000276:immunology; D002469:Cell Separation; D002474:Cell-Free System / Q000378:metabolism; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000201:enzymology / Q000276:immunology; D006801:Humans; D018796:Immunoconjugates / Q000378:metabolism / Q000494:pharmacology*; D007166:Immunosuppressive Agents / Q000378:metabolism / Q000494:pharmacology; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D007371:Interferon-gamma / Q000502:physiology; D007376:Interleukin-2 / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D007737:Kynurenine / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000201:enzymology / Q000276:immunology / Q000378:metabolism; D008213:Lymphocyte Activation / Q000276:immunology; D008562:Membrane Glycoproteins / Q000378:metabolism; D009000:Monocytes / Q000201:enzymology / Q000276:immunology; D011485:Protein Binding / Q000276:immunology; D012333:RNA, Messenger / Q000096:biosynthesis; D014364:Tryptophan / Q000378:metabolism / Q000502:physiology; D014366:Tryptophan Oxygenase / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D014369:Tryptophan-tRNA Ligase / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation / Q000276:immunology
D015703:Antigens, CD; D018122:B7-1 Antigen; D051940:B7-2 Antigen; C497964:CD86 protein, human; D018796:Immunoconjugates; D007166:Immunosuppressive Agents; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D007376:Interleukin-2; D008562:Membrane Glycoproteins; D012333:RNA, Messenger; D007737:Kynurenine; D000069594:Abatacept; D007371:Interferon-gamma; D014364:Tryptophan; D014366:Tryptophan Oxygenase; D014369:Tryptophan-tRNA Ligase