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

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.