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IFN-γ-indoleamine-2,3 dioxygenase acts as a major suppressive factor in 4-1BB-mediated immune suppression in vivo

By Young H. Kim, Beom K. Choi, Woo J. Kang, Kwang H. Kim, Sang W. Kang, Andrew L. Mellor, David H. Munn and Byoung S. Kwon


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-β was involved. Here, we have examined an alternative mechanism for the 4-1BB-mediated CD4+ T suppression, as the neutralization of TGF-β 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-γ-dependent manner. SEA-specific CD4+ T responses were suppressed partly by TGF-β-expressing CD8+ T cells, particularly CD11c+CD8+ T cells, but strongly inhibited by dendritic cells (DCs) expressing IDO. IFN-γ 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-γ 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-γ-dependent IDO induction and partially by TGF-β

Topics: Inflammation, Extracellular Mediators, and Effector Molecules
Publisher: The Society for Leukocyte Biology
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Provided by: PubMed Central
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