title: IFN-gamma-indoleamine-2,3 dioxygenase acts as a major suppressive factor in 4-1BB-mediated immune suppression in vivo.
abstract: It has been reported that 4-1BB triggering in vivo selectively suppressed the recall response of staphylococcal enterotoxin A (SEA)-specific CD4(+) T cells, in which CD8(+) T-derived TGF-beta was involved. Here, we have examined an alternative mechanism for the 4-1BB-mediated CD4(+) T suppression, as the neutralization of TGF-beta is only effective in rescuing the SEA-specific recall response at high cellular concentrations. We show that this selective suppression of CD4(+) T cells by 4-1BB triggering in vivo is mediated mainly by induction of indoleamine 2,3-dioxygenase (IDO) in an IFN-gamma-dependent manner. SEA-specific CD4(+) T responses were suppressed partly by TGF-beta-expressing CD8(+) T cells, particularly CD11c(+)CD8(+) T cells, but strongly inhibited by dendritic cells (DCs) expressing IDO. IFN-gamma that increased IDO in DCs was produced primarily from CD11c(+)CD8(+) T cells, which were expanded selectively by 4-1BB stimulation. CD4(+), CD8(+), and plasmacytoid DCs exerted a similar suppressive activity toward the SEA-specific CD4(+) T cells. Neutralization of IFN-gamma or IDO activity in vivo largely reversed the 4-1BB-mediated CD4(+) T suppression. Collectively, these data indicate that 4-1BB-dependent suppression of SEA-specific CD4(+) T responses was mediated mainly by IFN-gamma-dependent IDO induction and partially by TGF-beta.
authors.affiliation: Division of Cell and Immunobiology and R&D Center for Cancer Therapeutics, National Cancer Center, Kyonggi-do, Korea.
authors.forename: Young H
authors.initials: YH
authors.lastname: Kim
authors.forename: Beom K
authors.initials: BK
authors.lastname: Choi
authors.forename: Woo J
authors.initials: WJ
authors.lastname: Kang
authors.forename: Kwang H
authors.initials: KH
authors.lastname: Kim
authors.forename: Sang W
authors.initials: SW
authors.lastname: Kang
authors.forename: Andrew L
authors.initials: AL
authors.lastname: Mellor
authors.forename: David H
authors.initials: DH
authors.lastname: Munn
authors.forename: Byoung S
authors.initials: BS
authors.lastname: Kwon
mesh_terms: D053330:4-1BB Ligand / Q000276:immunology*; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D039521:CD11c Antigen / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology; D004768:Enterotoxins / Q000494:pharmacology; D007165:Immunosuppression Therapy; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000276:immunology*; D007371:Interferon-gamma / Q000276:immunology; D008213:Lymphocyte Activation; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016212:Transforming Growth Factor beta / Q000276:immunology
chemical_list: D053330:4-1BB Ligand; D000911:Antibodies, Monoclonal; D039521:CD11c Antigen; D004768:Enterotoxins; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D016212:Transforming Growth Factor beta; C026066:enterotoxin A, Staphylococcal; D007371:Interferon-gamma